Bile-acid derived compounds for providing sustained systemic concentrations of drugs after oral administration

ABSTRACT

This invention is directed to methods for providing sustained systemic concentrations of therapeutic or prophylactic agents such as GABA analogs following oral administration to animals. This invention is also directed to compounds and pharmaceutical compositions that are used in such methods.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/238,758, which was filed on Oct. 6, 2000; U.S.Provisional Application Serial No. 60/249,804, which was filed on Nov.17, 2000; and U.S. Provisional Application Serial No. 60/297,594 whichwas filed on Jun. 11, 2001, the disclosures of which are incorporated byreference in their entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention is directed to methods for providing sustainedsystemic concentrations of therapeutic or prophylactic agents such asGABA analogs following oral administration to animals. This invention isalso directed to compounds and pharmaceutical compositions that are usedin such methods.

[0004] References

[0005] The following publications, patents and patent applications arecited in this application as superscript numbers:

[0006] 1. Arya, P.; Burton, G. W. Bile acids for biological and chemicalapplications and processes for the production thereof. U.S. Pat. No.5,541,348, 1996.

[0007] 2. Baringhaus, K.-H.; Matter, H.; Stengelin, S.; Kramer, W.Substrate specificity of the ileal and hepatic Na⁺/bile acidcotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore modelfor the ileal Na⁺/bile acid cotransporter. J. Lipid Res. 1999, 40,2158-2168.

[0008] 3. Batta et al., J. Lipid Res. 1991, 32, 977-983.

[0009] 4. Bryans, J. S.; Wustrow, D. J. 3-Substituted GABA analogs withcentral nervous system activity: a review. Med. Res. Rev. 1999,19,149-177.

[0010] 5. Bundgaard, H. in Design of Prodrugs (Bundgaard, H. Ed.),Elsevier Science B. V., 1985, pp. 1-92.

[0011] 6. Fieser and Fieser's Reagents for Organic Synthesis, Volumes1-15 (John Wiley and Sons, 1991);

[0012] 7. Ho, N. F. H. Utilizing bile acid carrier mechanisms to enhanceliver and small intestine absorption. Ann. N. Y. Acad. Sci. 1987, 507,315-329.

[0013] 8. Jezyk, N.; Li, C.; Stewart, B. H.; Wu, X.; Bockbrader, H. N.;Fleisher, D. Transport of pregabalin in rat intestine and Caco-2monolayers. Pharm. Res. 1999, 16, 519-526.

[0014] 9. Kagedahl, M.; Swaan, P. W.; Redemann, C. T.; Tang, M.; Craik,C. S.; Szoka, F. C.; Oie, S. Use of the intestinal bile acid transporterfor the uptake of cholic acid conjugates with HIV-1 protease inhibitoryactivity. Pharm. Res. 1997, 14, 176-180.

[0015] 10. Kim, D.-C.; Harrison, A. W.; Ruwart, M. J.; Wilkinson, K. F.;Fisher, J. F.; Hidalgo, I. J.; Borchardt, R. T. Evaluation of bile acidtransporter in enhancing intestinal permeability of renin-inhibitorypeptides. J. Drug Targeting 1993, 1, 347-359.

[0016] 11. Kramer, W.; Wess, G.; Schubert, G.; Bickel, M.; Girbig, F.;Gutjahr, U.; Kowalewski, S.; Baringhaus, K.-H.; Enhsen, A.; Glombik, H.;Mullner, S.; Neckermarm, G.; Schulz, S.; Petzinger, E. Liver-specificdrug targeting by coupling to bile acids. J. Biol. Chem. 1992, 267,18598-18604.

[0017] 12. Kramer, W.; Wess, G.; Neckermann, G.; Schubert, G.; Fink, J.;Girbig, F.; Gutjahr, U.; Kowalewski, S.; Baringhaus, K.-H.; Boger, G.;Enhsen, A.; Falk, E.; Friedrich, M.; Glombik, H.; Hofftnann, A.;Pittius, C.; Urmann, M. Intestinal absorption of peptides by coupling tobile acids. J. Biol. Chem. 1994a, 269, 10621-10627.

[0018] 13. Kramer, W.; Wess, G.; Enhsen, A.; Bock, K.; Falk, E.;Hoffmann, A.; Neckerman, G.; Gantz, D.; Schulz, S.; Nickau, L.;Petzinger, E.; Turley, S.; Dietschy, J. M. Bile acid derived HMG-CoAreductase inhibitors. Biochim. Biophys. Acta 1994b, 1227, 137-154.

[0019] 14. Kramer, W.; Wess, G. Modified bile acid conjugates, and theiruse as pharmaceuticals. U.S. Pat. No. 5,462, 933, 1995.

[0020] 15. Kramer, W.; Wess, G. Bile acid conjugates of prolinehydroxylase inhibitors. U.S. Pat. No. 5,646,272, 1997a.

[0021] 16. Kramer, W.; Wess, G. Bile acid derivatives, processes fortheir preparation, and use as pharmaceuticals. U.S. Pat. No. 5,668,126,1997b.

[0022] 17. Kramer, W.; Stengelin, S.; Baringhaus, K.-H.; Enhsen, A.;Heuer, H.; Becker, W.; Corsiero, D.; Girbig, F.; Noll, R.; Weyland, C.Substrate specificity of the ileal and hepatic Na⁺/bile acidcotransporters of the rabbit. I. Transport studies with membranevesicles and cell lines expressing the cloned transporters. J. LipidRes. 1999, 40, 1604-1617.

[0023] 18. Kullak-Ublick, G. A.; Beuers, U.; Paumgartner, G.Hepatobiliary transport. J. Hepatology 2000, 32 (Suppl. 1), 3-18.

[0024] 19. Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989.

[0025] 20. March's Advanced Organic Chemistry, (John Wiley and Sons, 4thEdition),

[0026] 21. Navia, M. A.; Chaturvedi, P. R. Design principles for orallybioavailable drugs. Drug Discovery Today 1996, 1, 179-189.

[0027] 22. Opsenica et al, 2000

[0028] 23. Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),

[0029] 24. Petzinger, E.; Nickau, L.; Horz, J. A.; Schulz, S.; Wess, G.;Enhsen, A.; Falk, E.; Baringhaus, K.-H.; Glombik, H.; Hoffmann, A.;Mullner, S.; Neckermann, G.; Kramer, W. Hepatobiliary transport ofhepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitorsconjugated with bile acids. Hepatology 1995, 22, 1801-1811.

[0030] 25. Reiner, A. Process for preparing ursodeoxycholic acidderivatives and their inorganic and organic salts having therapeuticactivity. Eur. Patent 0 272 462 B1, 1992.

[0031] 26. Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989),

[0032] 27. Swaan, P. W.; Szoka, F. C.; Oie, S. Use of the intestinal andhepatic bile acid transporters for drug delivery. Adv. Drug DeliveryRev. 1996, 20, 59-82.

[0033] 28. Tsuji, A.; Tamai, I. Carrier-mediated intestinal transport ofdrugs. Pharm. Res. 1996, 13, 963-977.

[0034] 29. U.S. Provisional Patent Application Serial No. 60/238,758 ofGallop and Cundy, filed on Oct. 6, 2000

[0035] 30. Satzinger, et al., “Cyclic Amino Acid” U.S. Pat. No.4,024,175, May 17, 1977.

[0036] 31. Silverman, et al., “GABA and L-glutamic Acid Analogs forAntiseizure Treatment”, U.S. Pat. No. 5,563,175, Oct. 8, 1996.

[0037] 32. Alexander, et al., “Acyloxyisopropyl Carbamates as Prodrugsfor Amine Drug”s U.S. Pat. No. 5,684,018, Nov. 4, 1997.

[0038] 33. Horwell, et al., “Bridged Cyclic Amino Acids asPharmaceutical Agents”, U.S. Pat. No. 6,020,370, Feb. 1, 2000.

[0039] 34. Silverman, et al., “GABA and L-glutamine Acid Analogs forAntiseizure Treatment”, U.S. Pat. No. 6,028,214, Feb. 22, 2000.

[0040] 35. Horwell, et al., “Substituted Cyclic Amino Acids asPharmaceutical Agents”, U.S. Pat. No. 6,103,932, Aug. 15, 2000.

[0041] 36. Silverman, et al., “GABA and L-glutamine Acid Analogs forAntiseizure Treatment”, U.S. Pat. No. 6,117,906 Sep. 12, 2000.

[0042] 37. WO 92/09560 Published: Jun. 11, 1992 GABA and L-glutamic AcidAnalogs for Antiseizure Treatment

[0043] 38. WO 93/23383 Published: Nov. 25, 1993 GABA and L-Glutamic AcidAnalogs for Antiseizure Treatment

[0044] 39. WO 97129101 Published: Aug. 14, 1997 Novel Cyclic Amino Acidsas Pharmaceutical Agents

[0045] 40. WO 97/33858 Published: Sep. 18, 1997 Novel Substituted CyclicAmino Acids as Pharmaceutical Agents

[0046] 41. WO 97/33859 Published: Sep. 18, 1997 Novel Bridged CyclicAmino Acids As Pharmaceutical Agents

[0047] 42. WO 98/17627 Published: Apr. 30, 1998 Substituted GammaAminobutyric Acids as Pharmaceutical Agents

[0048] 43. WO 99108671 Published: Feb. 25, 1999 GABA analogs to preventand treat gastrointestinal damage

[0049] 44. WO 99/21824 Published: May 6, 1999 Cyclic Amino Acids andDerivatives Thereof Useful as Pharmaceutical Agents

[0050] 45. WO 99/31057 Published: Jun. 24, 19994(3)Substituted-4(3)-Aminomethyl-(Thio)Pyran or Piperidine Derivatives(=Gabapentin Analogues), Their Preparation and Their Use in theTreatment of Neurological Disorders

[0051] 46. WO 99/31074 Published: Jun. 24, 1999 Novel Amines asPharmaceutical Agents

[0052] 47. WO 99/31075 Published: Jun. 24, 19991-Substituted-1-Aminomethyl-Cycloalkane Derivatives (=GabapentinAnalogues), Their Preparation and Their Use in the Treatment ofNeurological Disorders

[0053] 48. WO 99/61424 Published: Dec. 2, 1999 ConformationallyConstrained Amino Acid CompoundsHaving Affinity for the Alpha2DeltaSubunit of a Calcium Channel

[0054] 49. WO 00/15611 Published: Mar. 23, 2000 Branched AlkylPyrrolidine-3-Carboxylic Acids

[0055] 50. WO 00/23067 Published: Apr. 27, 2000 Method for the Treatmentof Mania

[0056] 51. WO 00/31020 Published: Jun. 2, 2000 Improved Gamma AminoButyric Acid Analogs

[0057] 52. WO 00/50027 Published: Aug. 31, 2000 Gabapentin Derivativefor Preventing and Treating Visceral Pain

[0058] All of the above publications, patents and patent applicationsare herein incorporated by reference in their entirety to the sameextent as if each individual publication, patent or patent applicationwas specifically and individually indicated to be incorporated byreference in its entirety.

[0059] State of the Art

[0060] Rapid clearance of drugs from the systemic circulation representsa major impediment to effective clinical use of therapeutic and/orprophylactic compounds. Although multiple factors can influence thesystemic concentrations of drugs achieved following oral administration(including drug solubility, dissolution rate, first-pass metabolism,p-glycoprotein and related efflux mechanisms, hepatic/renal elimination,etc), rapid systemic clearance is a particularly significant reason forsuboptimal systemic exposure to many compounds. Rapid systemic clearancemay require that large doses of drug be administered to achieve atherapeutic or prophylatic effect. Such larger doses of the drug,however, may result in greater variability in drug exposure, morefrequent occurrence of side effects, or decrease in patient compliance.Frequent drug administration may also be required to maintain systemicdrug levels above a minimum effective concentration. This problem isparticularly significant for drugs that must be maintained in awell-defined concentration window to provide continuous therapeutic orprophylactic benefit while minimizing adverse effects (including forexample, antibacterial agents, antiviral agents, anticancer agents,anticonvulsants, anticoagulants, etc.).

[0061] Conventional approaches to extend the systemic exposure of drugswith rapid clearance involve the use of formulation or device approachesthat provide a slow or sustained release of drug within the intestinallumen. These approaches are well known in the art and normally requirethat the drug be well absorbed from the large intestine, where suchformulations are most likely to reside while releasing the drug. Drugsthat are amenable to conventional sustained release approaches must beorally absorbed in the intestine and traverse this epithelial barrier bypassive diffusion across the apical and basolateral membranes of theintestinal epithelial cells. The physicochemical features of a moleculethat favor its passive uptake from the intestinal lumen into thesystemic circulation include low molecular weight (e.g. <500 Da),adequate solubility, and a balance of hydrophobic and hydrophiliccharacter (logP generally 1.5-4.0).²¹

[0062] Polar or hydrophilic compounds are typically poorly absorbedthrough an animal's intestine as there is a substantial energeticpenalty for passage of such compounds across the lipid bilayers thatconstitute cellular membranes. Many nutrients that result from thedigestion of ingested foodstuffs in animals, such as amino acids, di-and tripeptides, monosaccharides, nucleosides and water-solublevitamins, are polar compounds whose uptake is essential to the viabilityof the animal. For these substances there exist specific mechanisms foractive transport of the solute molecules across the apical membrane ofthe intestinal epithelia. This transport is frequently energized byco-transport of ions down a concentration gradient. Solute transporterproteins are generally single sub-unit, multi-transmembrane spanningpolypeptides, and upon binding of their substrates are believed toundergo conformational changes which result in movement of thesubstrate(s) across the membrane.

[0063] Over the past 10-15 years, it has been found that a number oforally administered drugs are recognized as substrates by some of thesetransporter proteins, and that this active transport may largely accountfor the oral absorption of these molecules.²⁸ While in most instancesthe transporter substrate properties of these drugs were unanticipateddiscoveries made through retrospective analysis, it has been appreciatedthat, in principle, one might achieve good intestinal permeability for adrug by designing in recognition and uptake by a nutrient transportsystem. Drugs subject to active absorption in the small intestine areoften unable to passively diffuse across epithelial cell membranes andare too large to pass through the tight junctions that exist between theintestinal cells. These drugs include many compounds structurallyrelated to amino acids, dipeptides, sugars, nucleosides, etc. (forexample, many cephalosporins, ACE inhibitors, AZT, gabapentin,pregabalin, baclofen, etc.)

[0064] Numerous structural analogs of γ-aminobutyric acid (GABA) (1) andL-glutamic acid have been described in the art as pharmaceuticalagents.^(30,32,34-53) Examples include gabapentin (2), pregabalin (3),vigabatrin (4), and baclofen (5) (see FIG. 1). Gabapentin was designedas a lipophilic GABA analog and was launched in 1994 as ananticonvulsant therapy for the treatment of epilepsy. During humantrials and while in clinical use, it became apparent that gabapentininduced some other potentially useful therapeutic effects in chronicpain states and behavioral disorders. Gabapentin currently findssignificant off-label use in clinical management of neuropathic pain.Pregabalin has been shown to have a similar pharmacological profile togabapentin with greater potency in preclinical models of pain andepilepsy and is presently in Phase III clinical trials. It has beendemonstrated that gabapentin, pregabalin, and related structural analogsare absorbed specifically in the small intestine by the large neutralamino acid transporter (LNAA).⁸ Rapid systemic clearance of thesecompounds requires that they be dosed frequently to maintain atherapeutic or prophylactic concentration in the systemic circulation.⁴Conventional sustained release approaches have not been successfullyapplied to these drugs as they are not absorbed from the largeintestine. Thus there is a significant need for effective sustainedrelease versions of these drugs, particularly for the pediatric patientpopulation, since drug must be administered during school hours, raisingthe issues of compliance, liability, and social acceptance.

[0065] One attractive pathway that might be exploitable for sustainedoral delivery of drugs with rapid systemic clearance is theentero-hepatic circulation of bile acids.²⁷ Bile acids are hydroxylatedsteroids that play a key role in digestion and absorption of fat andlipophilic vitamins. After synthesis in the liver, they are secretedinto bile and excreted by the gall bladder into the intestinal lumenwhere they emulsify and help solubilize lipophilic substances. Bileacids are conserved in the body by active uptake from the terminal ileumvia the sodium-dependent transporter IBAT (or ASBT) and subsequenthepatic extraction by the transporter NTCP (or LBAT) located in thesinusoidal membrane of hepatocytes. This efficient mechanism to preservethe bile acid pool is termed the enterohepatic circulation (see FIG. 2).In man, the total bile acid pool (3-5 g) recirculates 6-10 times per daygiving rise to a daily uptake of approximately 20-30 g of bile acids.

[0066] The high transport capacity of the bile acid pathway has been akey reason for interest in this system for drug delivery purposes.Several papers have postulated that chemical conjugates of bile acidswith drugs could be used to provide liver site-directed delivery of adrug to bring about high therapeutic concentrations in the diseasedliver with minimization of general toxic reactions elsewhere in thebody; and gallbladder-site delivery systems of cholecystographic agentsand cholesterol gallstone dissolution accelerators.⁷ Several groups haveexplored these concepts in some detail, using the C-24 carboxylic acid,C-3, C-7, and C-12 hydroxyl groups of cholic acid (and other bile acids)as handles for chemically conjugating drugs or drug surrogates.^(10,11)

[0067] The most rigorous drug targeting studies using the bile acidtransport pathway to date relate to work with bile acid conjugates ofHMG-CoA reductase inhibitors.^(13,14,16,24) Coupling of the HMG-CoAreductase inhibitor HR 780 via an amide linkage to the C-3 position ofcholate, taurocholate and glycocholate afforded substrates for both theileal and liver bile acid transporter proteins (FIG. 3). Upon oraldosing of rats, the cholate conjugate S 3554 led to specific inhibitionof HMG-CoA reductase in the liver, and in contrast to the parentcompound HR 780, gave significantly reduced inhibition of the enzyme inextra-hepatic organs. Companion studies that looked at the tissuedistribution of radiolabeled drugs two hours after i.v., administrationthrough the mesenteric vein of rats also showed dramatically lowersystemic levels for the bile acid conjugate relative to the parent.Because inhibition of HMG-CoA reductase requires the presence of thefree carboxylic acid moiety in HR 780 this data was taken to indicatethat S 3554 served as a prodrug of HR 780, undergoing hydrolysis (andother uncharacterized metabolism) in the rat liver. Interestingly,uptake of S 3554 by liver did not appear to depend on the liver bileacid transporter NTCP (which prefers taurocholate conjugates), but mayinstead have involved another multispecific organic anion transportsystem on the sinusoidal hepatocyte membrane.

[0068] In summary, while the concept of harnessing the intestinal bileacid uptake pathway to enhance the absorption of poorly absorbed drugsis well appreciated, the existing art has merely demonstrated that bileacid-drug conjugates may be effectively trafficked to the liver andgenerally excreted into the bile, either unchanged or as some type ofmetabolite. The art gives no guidance as to how one prepares acomposition that exploits the bile acid transport pathway andsimultaneously provides therapeutically meaningful levels of a drugsubstance outside of the enterohepatic circulation. Furthermore, the artdoes not describe the potential use of the bile acid transport pathwayto achieve a circulating reservoir of conjugated drug that is slowlyreleased into the systemic circulation to provide sustainedconcentrations.

SUMMARY OF THE INVENTION

[0069] This invention is directed to the surprising discovery that thebile acid transport system can be utilized to provide sustained systemicconcentrations of orally delivered drugs to an animal. This invention,therefore, permits sustained therapeutic or prophylactic systemic bloodconcentrations of orally delivered drugs such as GABA analogs whichheretofore could not be achieved by oral administration.

[0070] Accordingly, in one of its method aspects, this invention isdirected to a method for achieving sustained therapeutic or prophylacticblood concentrations of a GABA analog or an active metabolite thereof inthe systemic circulation of an animal which method comprises orallyadministering to said animal a compound of formula (I):

[0071] Wherein:

[0072] R¹ and R² are independently hydrogen or hydroxy;

[0073] X is selected from the group consisting of hydroxy andD—Q^(a)—(T)— wherein:

[0074] T is —O— or —NH—;

[0075] Q^(a) is a covalent bond or a linking group that cleaves underphysiological conditions to release a GABA analog or active metabolitethereof into the systemic blood circulation of said animal, wherein saidlinker is not a linear oligopeptide consisting of 1, 2 or 3 α-aminoacids and/or β-amino acids; and

[0076] D is a GABA analog moiety preferably of the formula:

[0077]  wherein:

[0078] R³ is selected from the group consisting of hydrogen, anamino-protecting group, or a covalent bond linking the GABA analogmoiety to Q^(a);

[0079] R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to whichthey are attached form a heterocyclic ring;

[0080] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

[0081] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

[0082] R⁹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0083] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0084] R¹¹ is selected from the group consisting of carboxyl, amide,ester, sulfonamide, phosphonic acid, acidic heterocycle, sulfonic acid,hydroxamic acid and C(O)R¹²;

[0085] R¹² is a covalent bond linking the GABA analog moiety to Q^(a),provided only one of R³ and R¹² links D to Q^(a);

[0086] Z is selected from the group consisting of (a) a substitutedalkyl group containing a moiety which is negatively charged atphysiological pH which moiety is selected from the group consisting of—COOH, —SO₃H, —SO₂H, —P(O)(OR⁹)(OH), —OP(O)(OR¹⁹)(OH), —OSO₃H, whereinR⁹ is selected from the group consisting of alkyl, substituted alkyl,aryl and substituted aryl; and (b) a group of the formula:

—M—Q^(b)—D′

[0087]  wherein:

[0088] M is selected from the group consisting of —CH₂OC(O)— and—CH₂CH₂C(O)—;

[0089] Q^(b) is a covalent bond or a linking group which cleaves underphysiological conditions to release a GABA analog or active metabolitethereof into the systemic blood circulation of said animal, wherein saidlinker is not a linear oligopeptide consisting of 1, 2 or 3 α-aminoacids and/or β-amino acids; and

[0090] D′ is a GABA analog moiety preferably of the formula:

[0091]  wherein:

[0092] R^(3′) is selected from the group consisting of hydrogen, anamino-protecting group, or a covalent bond linking the moiety to Q^(b);

[0093] R^(4′) is hydrogen, or R^(4′) and R^(9′) together with the atomsto which they are attached form a heterocyclic ring;

[0094] R^(5′) and R^(6′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl;

[0095] R^(7′) and R^(8′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R^(7′)and R^(8′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring;

[0096] R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0097] R^(10′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0098] R^(11′) is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid, hydroxamic acid and C(O)R^(12′);

[0099] R^(12′) is a covalent bond linking the GABA analog moiety toQ^(b), provided only one of R^(3′) and R^(12′) links D to Q^(b); or

[0100] a pharmaceutically acceptable salt thereof;

[0101] provided that when X is hydroxy, then Z is a group of the formula—M—Q^(b)—D′.

[0102] Preferably R¹ and R² are both α-OH; or R¹ is β-OH and R² ishydrogen; or R¹ is α-OH and R² is hydrogen; or R¹ is hydrogen and R² isα-OH; or R¹ is β-OH and R² is α-OH; or R¹ and R² are both hydrogen.

[0103] X has either alpha or beta substitution relative to the A ring ofthe sterol.

[0104] Preferably, D—Q^(a)—(T)— and/or —M—Q^(b)—D′ are selected tocleave under physiological conditions at a rate to provide a therapeuticand/or prophylactic blood concentration of the GABA analog or activemetabolite thereof in the animal for a period of at least about 10%longer (more preferably at least 50% longer and still more preferably atleast 100% longer) than when the GABA analog is orally delivered byitself at an equivalent dose.

[0105] The selection of D—Q^(a)—(T)— and/or —M—Q^(b)—D′ are preferablymade relative to the activity, specificity and localization of enzymaticactivity within tissues that comprise the enterohepatic circulation suchthat the drug is released at a site from where it is made available tothe systemic circulation. For example, in one preferred embodiment,D—Q^(a)—(T)— and/or —M—Q^(b)—D′ are selected to contain one or moreester groups that permit cleavage of such groups by endogenous esteraseswithin such tissues. In another preferred embodiment, D—Q^(a)—(T)—and/or —M—Q^(b)—D′ are selected to contain one or more amide groupswhich amide groups permit cleavage of such groups by endogenousproteases. It will be appreciated by one skilled in the art that when Mor T is linked to a GABA analog (D) above via an amido group compoundsof formula I are provided wherein Q^(a) or Q^(b) is a covalent bond andhydrolysis of this bond in vivo provides for release of the GABA analogor active metabolite thereof.

[0106] Alternatively, Q^(a) and/or Q^(b) can be derived from a linkercompound having complementary reactive groups which covalently link theGABA analog to the bile acid. FIGS. 4 through 8 illustrate examples ofsuitable linking groups Q^(a) and Q^(b), where the linker is not alinear oligopeptide consisting of 1, 2 or 3 α-amino acids and/or β-aminoacids. Particularly preferred examples of suitable cleavable linkers foruse in this invention include structures of formulae (i) through (v) asshown below;

[0107] Wherein:

[0108] V is selected from the group consisting of NR²⁰, O, S andCR²¹R²²;

[0109] each s is independently 0 or 1;

[0110] r is 0, 1, 2, 3 or 4;

[0111] q is 1, 2, 3, 4, 5 or 6;

[0112] each R²⁰ is independently hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl;

[0113] each R²¹ and R²² is independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²¹ and R²² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or, when R²⁰ and R²² are present and are on adjacentatoms, then together with the atoms to which they are attached form aheterocyclyl or substituted heterocyclyl ring;

[0114] each R²³ and R²⁴ are independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²³ and R²⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0115] provided that when Q^(a) and/or Q^(b) is of formulae (i) or (ii),then when each V is NR²⁰ and each q is 1 or 2 then r is not 1, 2 or 3.

[0116] Preferred release rates of the GABA analog in each cycle are from5% to 95% and, more preferably, 10% to 95%.

[0117] When low release rates of the GABA analog or active metaboliteare employed, the continuous circulation of the compound of formula (I)allows for sustained release of the GABA analog or an active metabolitethereof by oral administration regardless of whether the GABA analog iscompletely or incompletely absorbed into the systemic blood circulation.

[0118] The methods of this invention are preferably achieved by use ofcompounds of formula (I). Accordingly, in one of its compositionaspects, this invention is directed to compounds of formula (I):

[0119] Wherein:

[0120] R¹ and R² are independently hydrogen or hydroxy;

[0121] X is selected from the group consisting of hydroxy andD—Q^(a)—(T)— wherein:

[0122] T is —O or —NH—;

[0123] Q^(a) is a covalent bond or a linking group; and

[0124] D is a GABA analog moiety preferably of the formula:

[0125]  wherein:

[0126] R³ is selected from the group consisting of hydrogen, anamino-protecting group, or a covalent bond linking the moiety to Q^(a);

[0127] R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to whichthey are attached form a heterocyclic ring;

[0128] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

[0129] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

[0130] R⁹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0131] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0132] R¹¹ is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid, hydroxamic acid and C(O)R¹²;

[0133] R¹² is a covalent bond linking the GABA analog moiety to Q^(a),provided only one of R³ and R¹² links D to Q^(a);

[0134] Z is selected from the group consisting of (a) a substitutedalkyl group containing a moiety which is negatively charged atphysiological pH which moiety is selected from the group consisting of—COOH, —SO₃H, —SO₂H, P(O)(OR¹⁹)(OH), OP(O)(OR¹⁹)(OH), —OSO₃H, whereinR¹⁹ is selected from the group consisting of alkyl, substituted alkyl,aryl and substituted aryl; and (b) a group of the formula:

—M—Q^(b)—D′

[0135]  wherein:

[0136] M is selected from the group consisting of —CH₂OC(O)— and—CH₂CH₂C(O)—;

[0137] Q^(b) is a covalent bond or a linking group which may cleaveunder physiological conditions to release a GABA analog or activemetabolite thereof into the systemic blood circulation of said animal;and

[0138] D′ is a GABA analog moiety preferably of the formula:

[0139]  wherein:

[0140] R^(3′) is selected from the group consisting of hydrogen, anamino-protecting group, or a covalent bond linking the GABA analog toQ^(b);

[0141] R^(4′) is hydrogen or R^(4′) and R^(9′) together with the atomsto which they are attached form a heterocyclic ring;

[0142] R^(5′) and R^(6′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl;

[0143] R^(7′) and R^(8′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R^(7′)and R^(8′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring;

[0144] R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0145] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0146] R¹¹ is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid, hydroxamic acid and C(O)R^(12′);

[0147] R^(12′) is a covalent bond linking the GABA analog moiety toQ^(b), provided only one of R^(3′) and R^(12′) links D to Q^(b); or

[0148] a pharmaceutically acceptable salt thereof;

[0149] provided that when X is hydroxy, then Z is a group of the formula—M—Q^(b)—D′; and

[0150] further provided that when X is hydroxy, M is —CH₂CH₂C(O)—, Q^(b)is a covalent bond and R^(11′) is carboxylic acid, then at least one ofR^(5′), R^(6′), R^(7′), R^(8′), R^(9′) and R^(10′) is other thanhydrogen.; and

[0151] yet further provided that neither Q^(a) nor Q^(b) is a linearoligopeptide comprised exclusively of 1, 2 or 3 α-amino acids and/orβ-amino acids.

[0152] While the above compounds include those wherein X is D—Q^(a)—(T)—and Z is —M—Q^(b)—D′, it is preferred that for compounds where Z is—M—Q^(b)—D′ then X is hydroxy. Similarly, it is preferred that forcompounds where X is D—Q^(a)—(T)— then Z is selected from the groupconsisting of —CH₂CH₂—COOH; —CH₂CH₂C(O)NHCH₂COOH and—CH₂CH₂C(O)NHCH₂CH₂SO₃H.

[0153] A particularly preferred group of compounds of Formula (I) isrepresented by Formula (II) shown below:

[0154] Wherein:

[0155] R¹ and R² are both α-OH;

[0156] R¹ is β-OH and R² is hydrogen;

[0157] R¹ is α-OH and R² is hydrogen;

[0158] R¹ is hydrogen and R² is α-OH;

[0159] R¹ is β-OH and R² is α-OH; or

[0160] R¹ and R² are both hydrogen;

[0161] A is —O— or —CH₂—;

[0162] D″ is a GABA analog moiety preferably selected from the groupconsisting of:

[0163] wherein:

[0164] R^(3′) and R^(11′) are defined above; and

[0165] Q^(b) is a covalent bond or a linker which may cleave underphysiological conditions to release said GABA analog or an activemetabolite thereof thereby providing a therapeutic or prophylacticsystemic blood concentration of said GABA analog or an active metabolitethereof in said animal, wherein said linker is not a linear oligopeptideconsisting of 1, 2 or 3 α-amino acids and/or β-amino acids; or

[0166] a pharmaceutically acceptable salt thereof.

[0167] Preferably, R^(11′) is CO₂H, CO₂Na or other pharmaceuticallyacceptable carboxylate salt.

[0168] Preferably, Q^(b) is selected to provide a therapeutic and/orprophylactic blood concentration in said animal for a period of at leastabout 10% longer (more preferably at least 50% longer and still morepreferably at least 100% longer) than when the GABA analog is orallydelivered by itself at an equivalent dose.

[0169] Preferably, Q^(b) is a covalent bond and D″ is linked via theamine to form an amido bond which cleaves under physiological conditionsto release the GABA analog.

[0170] When Q^(b) is a linker, it is preferably from 1-11 atoms inlength. More preferably, Q^(b) is a group of formula:

—[E—(F*)_(n)—G]_(m)—

[0171] Wherein:

[0172] m is an integer of from 1 to 4;

[0173] n is 0 or 1;

[0174] E is —NH— or —O—;

[0175] F* is selected from a group consisting of alkylene, substitutedalkylene, alkenylene, substituted alkenylene, alkynylene, substitutedalkynylene, cycloalkylene, substituted cycloalkylene, cycloalkenylene,substituted cycloalkenylene, arylene, substituted arylene,heteroarylene, substituted heteroarylene, heterocyclene and substitutedheterocyclene; and G is —OC(O)—, —C(O)— or —NH—.

[0176] Preferably, F* is selected from a group consisting of alkylene,alkenylene, alkynylene and alkylene substituted with a group selectedfrom the group consisting of —COOH, —SO₃H, —SO₂H, P(O)(OR¹⁹)(OH),OP(O)(OR¹⁹)(OH), —OSO₃H, wherein R¹⁹ is selected from the groupconsisting of alkyl, substituted alkyl, aryl and substituted aryl; andwhere one, two or three methylene groups are optionally replaced by acarboxy (—C(O)O—) group.

[0177] More preferably, Q^(b) is a covalent bond or a cleavable groupselected from the group consisting of structures of formulae (vi) to(x):

[0178] Wherein:

[0179] V and V* are independently NR²⁰, O, S or CR²R²²;

[0180] U is NR²⁰, O, S; R²⁵ is R²¹ or (CR²¹R²²)₁Z;

[0181] Z is selected from the group consisting of CO₂H, SO₃H, OSO₃H,SO₂H, P(O)(OR¹⁹)(OH), OP(O)(OR¹⁹)(OH);

[0182] s is 0 or 1;

[0183] r is 0, or 2;

[0184] k is 0, 1, 2, 3 or 4;

[0185] each q is 1, 2, 3, 4, 5 or 6;

[0186] 1 is 0 or 1;

[0187] R¹⁹ is selected from the group consisting of alkyl, substitutedalkyl, substituted aryl and substituted aryl;

[0188] R²⁰, R²¹ and R²² are independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²¹ and R²² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or, when R²⁰ and R²² are present and are on adjacentatoms, then together with the atoms to which they are attached form aheterocyclyl or substituted heterocyclyl ring;

[0189] R²³ and R²⁴ are independently hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R²³ and R²⁴together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0190] provided that when Q^(b) is of formula (vii), V and V* are NR²⁰,s is 1, k is 0 or 1, each q is either 1 or 2, and r is 0, 1 or 2 thenR²⁵ is Z.

[0191] Preferably, A is —CH₂—.

[0192] In another embodiment, a preferred group of compounds of Formula(I) are represented by Formula (IIIa) which is shown below:

[0193] Wherein:

[0194] R¹ and R² are both α-OH; R¹ is β-OH and R² is hydrogen; R¹ isα-OH and R² is hydrogen; R¹ is hydrogen and R² is α-OH; R¹ is β-OH andR² is α-OH; or R¹ and R² are both hydrogen;

[0195] T is —O— or —NH— and is either α- or β-;

[0196] D is a GABA analog moiety preferablyselected from the groupconsisting of:

[0197]  wherein R³ is defined above and R¹¹ is carboxylate or C(O)R¹²,wherein R¹² is a covalent bond linking D to Q′, provided that only oneof R³ and R¹² is a covalent bond linking D to Q′; and

[0198] Q′ is a covalent bond or a linker which may cleave underphysiological conditions to release said GABA analog or an activemetabolite thereof thereby providing a therapeutic or prophylacticsystemic blood concentration of said GABA analog or an active metabolitethereof in said animal, wherein said linker is not a linear oligopeptideconsisting of 1, 2 or 3 α-amino acids and/or β-amino acids;

[0199] R¹³ is a substituted alkyl group containing a moiety which isnegatively charged at physiological pH which moiety is selected from agroup consisting of —COOH, —SO₃H, —SO₂H, P(O)(OR¹⁹)(OH),OP(O)(OR¹⁹)(OH), —OSO₃H, wherein R¹⁹ is selected from the groupconsisting of alkyl, substituted alkyl, aryl and substituted aryl; or

[0200] a pharmaceutically acceptable salt thereof.

[0201] Preferably, R¹³ is —CH₂CH₂CO₂H, —CH₂CH₂C(O)NHCH₂COOH or—CH₂CH₂C(O)NH(CH₂)₂SO₃H or a sodium salt of the acid groups.

[0202] Preferably, Q′ is selected to provide a therapeutic and/orprophylactic blood concentration in said animal for a period of at leastabout 10% longer (more preferably at least 50% longer and still morepreferably at least 100% longer) than when the GABA analog is orallydelivered by itself at an equivalent dose.

[0203] More preferably, Q′ is a covalent bond that cleaves to releasethe GABA analog.

[0204] Still more preferably, Q′ is 1-20 atoms in length. Morepreferably, Q′ is a group of the formula:

—E′—(F′)_(nl)—G′—

[0205] Wherein:

[0206] n1 is 0 or 1;

[0207] G′ is —C(O)—, alkylene, —O—C(O)—, —NRC(O)— where R is hydrogen,alkyl or substituted alkyl;

[0208] F′ is selected from a group consisting of a covalent bond,alkylene, substituted alkylene, alkenylene, substituted alkenylene,alkynylene, substituted alkynylene, cycloalkylene, substitutedcycloalkylene, cycloalkenylene, substituted cycloalkenylene, arylene,substituted arylene, heteroarylene, substituted heteroarylene,heterocyclene and substituted heterocyclene; and

[0209] E′ is a covalent bond, —C(O)O— or —C(O)—.

[0210] More preferably, Q′ is a cleavable covalent bond or a groupselected from the group consisting of —C(O)— and the structures offormulae (i) through (v) as shown below;

[0211] Wherein:

[0212] V is selected from the group consisting of NR²⁰, O, S andCR²¹R²²;

[0213] each s is independently 0 or 1;

[0214] r is 0, 1, 2, 3 or 4;

[0215] each q is 1, 2, 3, 4, 5 or 6;

[0216] each R²⁰ is independently hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl;

[0217] each R²¹ and R²² is independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²¹and R²² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or, when R²⁰ and R²² are present and are on adjacentatoms, then together with the atoms to which they are attached form aheterocyclyl or substituted heterocyclyl ring;

[0218] each R²³ and R²⁴ are independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²³ and R²⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0219] provided that when Q′ is of formulae (i) or (ii), then when eachV is NR²⁰ and each q is 1 or 2 then r is not 1, 2 or 3.

[0220] In yet another embodiment, a preferred group of compounds ofFormula (I) are represented by Formula (IlIb) shown below:

[0221] Wherein:

[0222] R¹ and R² are both α-OH; R¹ is β-OH and R² is hydrogen; R¹ isα-OH and R² is hydrogen; R¹ is hydrogen and R² is α-OH; R¹ is β-OH andR² is α-OH; or R¹ and R² are both hydrogen;

[0223] T is —O— or —NH— and is either alpha or beta;

[0224] D is a GABA analog moiety preferably selected from the groupconsisting of:

[0225] Wherein:

[0226] R³ and R¹¹ are defined above;

[0227] R¹⁵ is hydrogen or an amino protecting group which ishydrolysable in vivo; and

[0228] Q″ is a covalent bond or a linker which may cleave underphysiological conditions to release said GABA analog or an activemetabolite thereof thereby providing a therapeutic or prophylacticsystemic blood concentration of said GABA analog or an active metabolitethereof in said anima, wherein said linker is not a linear oligopeptideconsisting of 1, 2 or 3 α-amino acids and/or β-amino acids 1;

[0229] R¹⁴ is carboxyl or alkylamido substituted with a substituentselected from the group consisting of —COOH, —SO₃H, —SO₂H,P(O)(OR¹⁹)(OH), OP(O)(OR¹⁹)(OH), —OSO₃H, wherein R¹⁹ is selected fromthe group consisting of alkyl, substituted alkyl, aryl and substitutedaryl; or

[0230] a pharmaceutically acceptable salt thereof.

[0231] Preferably, R¹⁴ is carboxyl, —C(O)NHCH₂CO₂H, or —C(O)NH(CH₂)₂SO₃Hor a sodium salt of the acid groups.

[0232] Preferably, R¹⁵ is hydrogen, —C(O)—O-R¹⁶ where R¹⁶ is alkyl, morepreferably methyl, ethyl, or —C(O)(CR²¹R²²)NHR²⁰ where R²⁰, R²¹ and R²²are defined as above.

[0233] Preferably, Q″ is selected to provide a therapeutic and/orprophylactic blood concentration in said animal for a period of at leastabout 10% longer (more preferably at least 50% longer and still morepreferably at least 100% longer) than when the GABA analog is orallydelivered by itself.

[0234] Preferably, Q″ is a covalent bond that cleaves to release theGABA analog.

[0235] Preferably, Q″ is a cleavable covalent bond or a group selectedfrom —C(O)— and the structures of formulae (i) through (v) as shownbelow;

[0236] Wherein:

[0237] V is selected from the group consisting of NR²⁰, O, S andCR²¹R²²;

[0238] each s is independently 0 or 1;

[0239] r is 0, 1, 2, 3 or 4;

[0240] q is 1, 2, 3, 4, 5 or 6;

[0241] each R²⁰ is independently hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl;

[0242] each R²¹ and R²² is independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²¹ and R²² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or, when R²⁰ and R²² are present and are on adjacentatoms, then together with the atoms to which they are attached form aheterocyclyl or substituted heterocyclyl ring;

[0243] each R²³ and R²⁴ are independently hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²³ and R²⁴ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0244] provided that when Q″ is of formulae (i) or (ii), then when eachV is NR²⁰ and each q is 1 or 2 then r is not 1, 2 or 3.

[0245] Particularly preferred compounds of Formula IIIa and Formula IIIbare those selected from the group consisting of:

[0246] Wherein:

[0247] R¹ and R² are as defined above; or

[0248] pharmaceutically acceptable salts thereof.

[0249] The compounds described above are preferably administered aspharmaceutical compositions comprising the drug/cleavablelinker/transporter compounds described above and a pharmaceuticallyacceptable excipient.

[0250] For compounds of Formula I where X is hydroxyl and compounds ofFormula II, the moiety —Q^(b)—D′ or —Q^(b)—D″ when taken together mostpreferably contains a moiety which is negatively charged atphysiological pH, located from 5 to 15 atoms from C-22 of the bile acidnucleus, which moiety is selected from the group consisting Of CO₂H,SO₃H, OSO₃H, SO₂H, P(O)(OR¹⁹)(OH), OP(O)(OR¹⁹)(OH) and pharmaceuticallyacceptable salts thereof, wherein R¹⁹ is defined above.

[0251] Particularly preferred compounds can be further represented asstructures of Formulae (V)-(XV) illustrated in FIGS. 4-6, where each ofR¹, R², R^(5′), R^(6′), R^(7′), R^(8′), R^(9′), R^(10′) and R^(11′) areas defined in the Summary of the Invention.

[0252] Particularly preferred compounds can be further represented asstructures of Formulae (XVI)-(XXVI) illustrated in FIGS. 7 and 8, whereeach of R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(5′), R^(6′),R^(7′), R^(8′), R^(9′) and R^(10′) are as defined in the Summary of theInvention.

[0253] Compounds of the formulae (V)-(XXVI) contain a variety ofcleavable linker functionalities (attached to GABA analogs includingamide linkages [compounds (V)-(IX), (XX), (XXII), (XXIV) and (XXVI);carbamate linkages [compounds (X)-(XII), (XVII) and (XXIII)];acyloxyalkyl carbamate linkages [compounds (XIII)-(XV), (XXI) and (XXV)]as well as compounds that have two different linkages that must becleaved to release the drug [compounds (XVI)-(XVII)].

[0254] The compounds described above are preferably administered aspharmaceutical compositions comprising the drug/cleavablelinker/transporter compounds described above and a pharmaceuticallyacceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0255]FIG. 1 illustrates structural analogs of y-aminobutyric acid(GABA).

[0256]FIG. 2 illustrates the enterohepatic circulation with keytransporter proteins identified which mediate bile acid circulation.

[0257]FIG. 3 illustrates the prior art HMG-CoA reductase inhibitor HR780 as well as prior art conjugates employing the lactone-Opened ring ofHR 780 coupled to a bile acid.

[0258] FIGS. 4-6 illustrate bile acids with modified C-17 side chainsthat are especially preferred compounds of formula (I-II).

[0259]FIGS. 7 and 8 illustrate 3-substituted bile acids that areespecially preferred compounds of formula (I-III).

[0260]FIG. 9 illustrates the effect of substrate concentration on theactive uptake of (8) or glycocholate by IBAT-transfected CHO cells invitro. Non-specific uptake by untransfected CHO K1 cells has beensubtracted.

[0261]FIG. 10 illustrates the effect of substrate concentration on theactive uptake of (8) or glycocholate by LBAT-transfected CHO cells invitro. Non-specific uptake by untransfected CHO K1 cells has beensubtracted.

[0262] FIGS. 11-33 illustrate reaction sequences for preparation ofcompounds of formulae (I)-(III).

DETAILED DESCRIPTION OF THE INVENTION

[0263] This invention is directed to methods for providing sustainedsystemic concentrations of therapeutic or prophylactic agents followingoral administration to animals. This invention is also directed tocompounds and pharmaceutical compositions that are used in such methods.However, prior to describing this invention in further detail, thefollowing terms will first be defined:

[0264] Definitions

[0265] As used herein, the term “animal” refers to various species suchas mammalian and avian species including, by way of example, humans,cattle, sheep, horses, dogs, cats, turkeys, chicken, and the like.Preferably, the animal is a mammal and even more preferably is a human.

[0266] “GABA analog” preferably refers to a compound of one of thefollowing formulae:

[0267] Wherein

[0268] R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms to whichthey are attached form a heterocyclic ring;

[0269] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

[0270] R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R⁷ and R⁸ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclic or substituted heterocyclic ring;

[0271] R⁹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0272] R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0273] R¹¹ is selected from the group consisting of carboxyl, amide,ester, sulfonamide, phosphonic acid, acidic heterocycle, sulfonic acid,hydroxamic acid and C(O)R¹²;

[0274] R¹² is a covalent bond linking the GABA analog moiety to Q^(a),provided only one of R³ and R¹² links D to Q^(a)

[0275] R^(4′) is hydrogen, or R^(4′) and R^(9′) together with the atomsto which they are attached form a heterocyclic ring;

[0276] R^(5′) and R^(6′)are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl;

[0277] R^(7′) and R^(8′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R^(7′)and R^(8′) together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclic or substitutedheterocyclic ring;

[0278] R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0279] R^(10′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl;

[0280] R^(11′) is selected from the group consisting of carboxylic acid,carboxylic amide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid, hydroxamic acid and C(O)R¹²;

[0281] R^(12′) is a covalent bond linking the GABA analog moiety toQ^(b), provided only one of R^(3′) and R^(12′) links D to Q^(b).

[0282] “Orally delivered drugs” refer to drugs which are administered toan animal in an oral form, preferably, in a pharmaceutically acceptablediluent. Oral delivery includes ingestion of the drug as well as oralgavage of the drug.

[0283] “Systemic bioavailability” refers to the rate and extent ofsystemic exposure to a drug or a metabolite thereof as reflected by thearea under the systemic blood concentration versus time curve.

[0284] “Translocation across the intestinal wall” refers to movement ofa drug or drug conjugate by a passive or active mechanism, or both,across an epithelial cell membrane of any region of the gastrointestinaltract.

[0285] “Active metabolite of a drug” refers to products of in vivomodification of the compound of formula (I-IIIa and b) which havetherapeutic or prophylactic effect.

[0286] “Therapeutic or prophylactic blood concentrations” refers tosystemic exposure to a sufficient concentration of a drug or an activemetabolite thereof over a sufficient period of time to effect diseasetherapy or to prevent the onset or reduce the severity of a disease inthe treated animal.

[0287] “Treating” a particular disease or disorder means reducing thenumber of symptoms and/or severity of symptoms of the disease, and/orreducing or limiting the further progression of the disease.

[0288] “Preventing” a disease or disorder means preventing or inhibitingthe onset or occurrence of the disease or disorder.

[0289] “Sustained release” refers to release of a drug or an activemetabolite thereof into the systemic circulation over a prolonged periodof time relative to that achieved by oral administration of aconventional formulation of the drug.

[0290] “Tissue of the enterohepatic circulation” refers to the blood,plasma, intestinal contents, intestinal cells, liver cells, biliarytract or any fraction, suspension, homogenate, extract or preparationthereof.

[0291] “Conjugating” refers to the formation of a covalent bond.

[0292] “Bile acid transport system” refers to any membrane transporterprotein capable of causing a bile acid or a derivative thereof to betranslocated across a membrane of a cell of the gastrointestinal tractor liver.

[0293] “Active transport or active transport mechanism” refers to themovement of molecules across cellular membranes that:

[0294] a) is directly or indirectly dependent on an energy mediatedprocess (i.e. driven by ATP hydrolysis, ion gradient, etc); or

[0295] b) occurs by facilitated diffusion mediated by interaction withspecific transporter proteins; or

[0296] c) occurs through a modulated solute channel.

[0297] “A moiety selected to permit a compound of formula (I), (II) or(III) to be translocated across the intestinal wall of an animal via thebile acid transport system” refers to compounds which, when conjugatedto the drug/cleavable linker moiety, are translocated across theintestinal wall via the bile acid transport system. Evaluation of whichcandidate compounds can be so translocated across the intestinal wallcan be conducted by the in vitro assay set forth in Example 42 below.

[0298] “Practical dosage regimen” refers to a schedule of drugadministration that is practical for a patient to comply with. For humanpatients, a practical dosage regimen for an orally administered drug islikely to be an aggregate dose of less than 10 g/day.

[0299] “Acidic heterocycle” refers to a reprotonatable heterocyclehaving a pKa less than 7.0. Examples of such heterocycles include thefollowing:

[0300] “Cleavable linker” refers to linkers that contain one or morefunctional groups which permit cleavage of such groups in vivo by, forexample, endogenous enzymes. Preferably, the functional group subject tocleavage in the cleavable linker is attached adjacent the drug moiety,D, such that upon cleavage, the free drug is released. The cleavablelinker preferably comprises one or more functional groups such as estergroups, amide groups, glycolamide ester groups, amidomethyl esters,acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, and the like. Withthe proviso that the cleavable linker is not an oligo peptide of one tothree amino acids in length.

[0301] The term “drug/cleavable linker/transporter compound” (whichsometimes is referred to as the “drug-transporter compound”,“drug/linker/transporter compound” and “drug/cleavablelinker/transporter conjugate” refers to compounds of formulae (I), (II)and/or (III).

[0302] “Linear oligopeptide” refers to an amide oligomer comprisingeither a terminal amino group or a terminal carboxylic acid group or(preferably) both a terminal amino group and a terminal carboxylic acidgroup, which oligomer is formed by condensation of the terminal aminoresidue of at least one amino acid (or GABA analog) with the terminalcarboxylic acid residue of at least a second amino acid (or GABAanalog). In addition to the GABA analog, the amino acids comprising theoligopeptide are optionally either α-amino acids, β-amino acids, or amixture of α-amino acids and β-amino acids. Note that when an α-aminoacid additionally contains either a β-amino group or a β-carboxylic acidgroup (e.g. as in aspartic acid) a linear oligopeptide formed from suchan amino acid is intended to imply that it is the α-amine orα-carboxylic acid moiety (or both) of such residue that is involved inamide formation.

[0303] “α-Amino acids” are molecules of the formula:

HNR¹⁸—CR²¹R²²—C(O)OH:

[0304] Wherein:

[0305] R¹⁸ is hydrogen or R¹⁸ and R²¹ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0306] R²¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R²¹ and R²² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring.

[0307] “β-Amino acids” are molecules of formula

HNR¹⁸—(CR²¹R²²)—(CR³¹R³²)—C(O)OH:

[0308] Wherein:

[0309] R¹⁸ is hydrogen or R¹⁸ and R²¹ together with the atoms to whichthey are attached form a heterocyclyl ring;

[0310] R²¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R²¹ and R²² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or R²¹ andR³¹ together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring;

[0311] R²² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl;

[0312] R³¹ is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R³¹ and R³² together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring;

[0313] R³² is hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl.

[0314] “Derived from a compound” refers to a moiety that is structurallyrelated to such a compound. The structure of the moiety is identical tothe compound except at 1 or 2 positions. At these positions either ahydrogen atom attached to a heteroatom, or a hydroxyl moiety of acarboxylic, phosphonic, phosphoric or sulfonic acid group has beenreplaced with a covalent bond that serves as a point of attachment toanother moiety.

[0315] “Amino-protecting group” or “amino-blocking group” refers to anygroup which when bound to one or more amino groups prevents reactionsfrom occurring at these amino groups and which protecting groups can beremoved by conventional chemical steps to reestablish the amino group.The particular removable blocking group is not critical and preferredamino blocking groups include, by way of example only, t-butyoxycarbonyl(t-BOC), benzyloxycarbonyl (CBZ), and the like.

[0316] “Carboxyl-protecting group” or “carboxyl-blocking group” refersto any group which when bound to one or more carboxyl groups preventsreactions from occurring at these groups and which protecting groups canbe removed by conventional chemical steps to reestablish the carboxylgroup. The particular removable blocking group is not critical andpreferred carboxyl blocking groups include, by way of example only,esters of the formula —COOR″ where R″ is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, substituted aryl, alkaryl, substituted alkaryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic.

[0317] “Alkyl” refers to alkyl groups preferably having from 1 to 20carbon atoms and more preferably 1 to 6 carbon atoms. This term isexemplified by groups such as methyl, t-butyl, n-heptyl, octyl, dodecyland the like.

[0318] “Substituted alkyl” refers to an alkyl group, preferably of from1 to 20 carbon atoms, having from 1 to 5 substituents selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic,cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substitutedheteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substitutedheteroarylamino, mono- and di-heterocyclic amino, mono- anddi-substituted heterocyclic amino, unsymmetric di-substituted amineshaving different substituents selected from the group consisting ofalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkyl/substituted alkyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0319] “Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0320] “Substituted alkoxy” refers to the group “substituted alkyl-O—”.

[0321] “Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)— cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O), heterocyclic-C(O)—, and substitutedheterocyclic-C(O)— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0322] “Acylamino” refers to the group —C(O)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0323] “Thiocarbonylarnino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0324] “Acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O— wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0325] “Alkenyl” refers to alkenyl group preferably having from 2 to 20carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkenyl unsaturation.

[0326] “Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(Q)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0327] “Alkenyloxy” refers to the group —O-alkenyl.

[0328] “Substituted alkenyloxy” refers to the group —O-substitutedalkenyloxy.

[0329] “Alkynyl” refers to alkynyl group preferably having from 2 to 20carbon atoms and more preferably 3 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkynyl unsaturation.

[0330] “Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylarnino, thiocarbonylarnino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0331] “Alkylene” refers to a divalent alkylene group preferably havingfrom 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. Thisterm is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—)and the like.

[0332] “Substituted alkylene” refers to alkylene groups having from 1 to5 substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0333] “Alkenylene” refers to a divalent alkenylene group preferablyhaving from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atomsand having from 1 to 2 sites of alkenyl unsaturation. This term isexemplified by groups such as ethenylene (—CH═CH—), propenylene(—CH₂CH═CH—), and the like.

[0334] “Substituted alkenylene” refers to alkenylene groups having from1 to 5 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0335] “Alkynylene” refers to a divalent alkynylene group preferablyhaving from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atomsand having from 1 to 2 sites of alkynyl unsaturation. This term isexemplified by groups such as ethynylene, propynylene and the like.

[0336] “Substituted alkynylene” refers to alkynylene groups having from1 to 5 substituents selected from the group consisting of alkoxy,substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino,amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)arnino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and substituted alkenyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0337] “Amidino” refers to the group H₂NC(═NH)— and the term“alkylamidino” refers to compounds having 1 to 3 alkyl groups (e.g.,alkylHNC(═NH)—).

[0338] “Thioamidino” refers to the group RSC(═NH)— where R is hydrogenor alkyl.

[0339] “Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substitutedalkyl, —NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0340] “Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0341] “Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0342] “Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0343] “Aminocarbonylamino” refers to the groups —NRC(O)NRR,—NRC(O)NR-alkyl, —NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl,—NRC(O)NR-substituted alkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substitutedalkynyl, —NRC(O)NR-aryl, —NRC(O)NR-substituted aryl,—NRC(O)NR-cycloalkyl, —NRC(O)NR-substituted cycloalkyl,—NRC(O)NR-heteroaryl, and —NRC(O)NR-substituted heteroaryl,—NRC(O)NR-heterocyclic, and —NRC(O)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0344] “Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0345] “Aryl” or “Ar” refers to a monovalent unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)which condensed rings may or may not be aromatic (e.g.,2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like).Preferred aryls include phenyl and naphthyl.

[0346] “Substituted aryl” refers to aryl groups which are substitutedwith from 1 to 3 substituents selected from the group consisting ofhydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino,aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino,aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0347] “Arylene” refers to a divalent unsaturated aromatic carbocyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g.,phenylene) or multiple condensed rings (e.g., naphthylene or anthrylene)which condensed rings may or may not be aromatic. Preferred arylenesinclude phenylene and naphthylene.

[0348] “Substituted arylene” refers to arylene groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0349] “Aryloxy” refers to the group aryl-O— which includes, by way ofexample, phenoxy, naphthoxy, and the like.

[0350] “Substituted aryloxy” refers to substituted aryl-O— groups.

[0351] “Aryloxyaryl” refers to the group -aryl-O-aryl.

[0352] “Substituted aryloxyaryl” refers to aryloxyaryl groupssubstituted with from 1 to 3 substituents on either or both aryl ringsselected from the group consisting of hydroxy, acyl, acylamino,thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylarnidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0353] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbonatoms having a single cyclic ring including, by way of example,cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Thisdefinition includes bridged groups such as bicyclo[2.2.1]heptane andbicyclo[3.3.1]nonane.

[0354] “Cycloalkyloxy” refers to —O-cycloalkyl.

[0355] “Cycloalkenyl” refers to cyclic alkenyl groups of frm 3 to 8carbon atoms having a single cyclic ring.

[0356] “Cycloalkenyloxy” refers to —O-cycloalkenyl.

[0357] “Substituted cycloalkyl” and “substituted cycloalkenyl” refers toan cycloalkyl or cycloalkenyl group, preferably of from 3 to 10 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic and substituted alkynyl groups having aminogroups blocked by conventional blocking groups such as Boc, Cbz, formyl,and the like or alkynyl/substituted alkynyl groups substituted with—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substitutedalkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0358] “Substituted cycloalkyloxy” and “substituted cycloalkenyloxy”refers to —O-substituted cycloalkyl and —O-substituted cycloalkenyloxyrespectively.

[0359] “Cycloalkylene” refers to divalent cyclic alkylene groups of from3 to 8 carbon atoms having a single cyclic ring including, by way ofexample, cyclopropylene, cyclobutylene, cyclopentylene, cyclooctyleneand the like.

[0360] “Cycloalkenylene” refers to a divalent cyclic alkenylene groupsof frm 3 to 8 carbon atoms having a single cyclic ring.

[0361] “Substituted cycloalkylene” and “substituted cycloalkenylene”refers to a cycloalkylene or cycloalkenylene group, preferably of from 3to 8 carbon atoms, having from 1 to 5 substituents selected from thegroup consisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy,acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0362] “Cycloalkoxy” refers to —O-cycloalkyl groups.

[0363] “Substituted cycloalkoxy” refers to —O-substituted cycloalkylgroups.

[0364] “Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0365] “N,N-Dimethylcarbamyloxy” refers to the group —OC(O)N(CH₃)₂.

[0366] “Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂-heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0367] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

[0368] “Heteroaryl” refers to an aromatic carbocyclic group of from 2 to10 carbon atoms and 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur within the ring. Suchheteroaryl groups can have a single ring (e.g., pyridyl or furyl) ormultiple condensed rings (e.g., indolizinyl or benzothienyl). Preferredheteroaryls include pyridyl, pyrrolyl, indolyl and furyl.

[0369] “Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamnino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0370] “Heteroarylene” refers to a divalent aromatic carbocyclic groupof from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur within the ring. Suchheteroarylene groups can have a single ring (e.g., pyridylene orfurylene) or multiple condensed rings (e.g., indolizinylene orbenzothienylene). Preferred heteroarylenes include pyridylene,pyrrolylene, indolylene and furylene.

[0371] “Substituted heteroarylene” refers to heteroarylene groups whichare substituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and amino groups on the substituted aryl blocked byconventional blocking groups such as Boc, Cbz, formnyl, and the like orsubstituted with —SO₂NRR where R is hydrogen or alkyl.

[0372] “Heteroaryloxy” refers to the group —O-heteroaryl and“substituted heteroaryloxy” refers to the group —O-substitutedheteroaryl. “Heterocycle” or “heterocyclic” refers to a saturated orunsaturated group having a single ring or multiple condensed rings, from1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from thegroup consisting of nitrogen, sulfur or oxygen within the ring wherein,in fused ring systems, one or more the rings can be aryl or heteroaryl.

[0373] “Substituted heterocyclic” refers to heterocycle groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS()₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-aikylamino, mono- and di-(substituted aikyl)amino, mono- anddi-arylamlino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0374] Examples of heterocycles and heteroaryls include, but are notlimited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

[0375] “Heterocyclene” refers to a divalent saturated or unsaturatedgroup having a single ring or multiple condensed rings, from 1 to 10carbon atoms and from 1 to 4 hetero atoms selected from the groupconsisting of nitrogen, sulfur or oxygen within the ring wherein, infused ring systems, one or more the rings can be aryl or heteroaryl.

[0376] “Substituted heterocyclene” refers to heterocyclene groups whichare substituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-aryla—ino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom the group consisting of alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0377] “Heterocyclyloxy” refers to the group —O-heterocyclic and“substituted heterocyclyloxy” refers to the group —O-substitutedheterocyclic.

[0378] “Thiol” refers to the group —SH.

[0379] “Thioalkyl” refers to the groups —S-alkyl.

[0380] “Substituted thioalkyl” refers to the group —S-substituted alkyl.

[0381] “Thiocycloalkyl” refers to the groups —S-cycloalkyl.

[0382] “Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

[0383] “Thioaryl” refers to the group —S-aryl and “substituted thioaryl”refers to the group —S-substituted aryl.

[0384] “Thioheteroaryl” refers to the group —S-heteroaryl and“substituted thioheteroaryl” refers to the group —S-substitutedheteroaryl.

[0385] “Thioheterocyclic” refers to the group —S-heterocyclic and“substituted thioheterocyclic” refers to the group —S-substitutedheterocyclic.

[0386] “Amino” refers to the —NH₂ group.

[0387] “Substituted amino” refers to the —NR′R″ group wherein R′ and R″are independently hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic or where R′ and R″,together with the nitrogen atom pendent thereto, form a heterocyclicring.

[0388] “Pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts of a compound of Formulae (I), (II) or (III) whichsalts are derived from a variety of organic and inorganic counter ionswell known in the art and include, by way of example only, sodium,potassium, calcium, magnesium, ammonium, tetraalkylammonium, and thelike; and when the molecule contains a basic functionality, salts oforganic or inorganic acids, such as hydrochloride, hydrobromide,tartrate, mesylate, acetate, maleate, oxalate and the like.

[0389] Utility

[0390] The compounds and methods described herein permit thedrug/cleavable linker/transporter compounds to provide sustained releaseof the GABA analog or active metabolite thereof relative to oral dosingwith the parent drug itself In this regard, enterohepatic recycling ofthe bile acid conjugates creates a reservoir for the active agent.

[0391] GABA analogs are useful in treating epilepsy, faintness attacks,hypokinesia, cranial disorders, neurodegnerative disorders, depression,anxiety, panic, pain, neuropatholgical disorders, gastrointestinaldamage, inflammation and irritable bowel disease. See, for example, WO99/31075 which is incorporated herein by reference in its entirety.

[0392] Compounds of this invention which employ a non-cleavable linkercan be used for diagnostic purposes to evaluate the relative transportof such compounds across the intestinal wall thereby providing clinicalinformation regarding transport efficacy and the like.

[0393] General Synthetic Scheme

[0394] Compounds of this invention can be made by the methods depictedin the reaction schemes shown below.

[0395] The starting materials and reagents used in preparing thesecompounds are either available from commercial suppliers such as AldrichChemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure.

[0396] The starting materials and the intermediates of the reaction maybe isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

[0397] Preparation of Compounds of Formula (I)

[0398] Schemes A-C describe alternative methods to prepare the compoundsof Formula (I). where X, R¹ and R² are hydroxy, Z is a group of formula—M—Q^(b)—D′ where M is —CH₂CH₂—C(O)—, Q^(b) is a cleavable bond, and D′is a GABA analog moiety related to formula (a) that is attached to Mthrough its terminal amino group can be prepared as illustrated anddescribed in Scheme A below.

[0399] A compound of Formula (I) where X¹, R¹ and R² are hydroxy, Z is agroup of formula —M—Q^(b)—D′ where M is —CH₂CH₂—C(O)—, Q^(b) is acleavable bond, and D′ is a GABA analog moiety related to formula (a)that is attached to M through its terminal amino group can be preparedby first converting commercially available cholic acid A to an activatedacid derivative B where Y is a suitable leaving group, followed bytreatment with an amine of formula (a) (where R^(3′) is hydrogen) toprovide a compound of Formula (I). Compound B where Y is a leaving groupsuch as —OCO₂Et can be prepared by treating A with ethyl chloroformatein the presence of a tertiary organic amine such as triethylamine,tributylamine, diisopropylethylamine and the like. The reaction istypically carried out in a suitable organic solvent such astetrahydrofuran and at low temperatures e.g., between −15 to 0° C. Itwill be recognized by a person skilled in the art that compound A canalso be converted to an activated acid B in the presence of other acidactivating agents such as dicyclohexylcarbodiimide, and the like. Thedisplacement of leaving group Y with an amine of formula (a) is carriedout by adding (a) to the activated acid B, in the presence of an aqueousinorganic base such as sodium hydroxide, sodium bicarbonate, potassiumhydroxide and the like.

[0400] Amines of formula (a) are either commercially available or theycan be prepared by methods well known in the art of organic chemistry.For example, 1-aminomethyl-1-cyclohexane acetic acid is commerciallyavailable. 2-Aminomethyl-4-methylpentanoic acid can be prepared by themethods described in U.S. Pat. No. 5,563,175.

[0401] Compounds of Formula (II) where R¹, and R² are hydroxy, A is —O—,Q^(b) is a cleavable bond, and D′ is a GABA analog moiety related toformula (a) can be prepared as illustrated and described in Scheme Bbelow.

[0402] Scheme B

[0403] A compound of Formula (II) where R¹ and R² are hydroxy, A is —O—,Q^(b) is a cleavable bond, and D″ is a GABA analog moiety related toformula (a) can be prepared by converting 23-nor-562 -cholanic acid D(prepared according to the method described in U.S. Pat. No. 5,541,348)to a corresponding hydroxy derivative of formula E. Treatment of E withan isocyanate of formula F then provides a compound of Formula (I).Typically, R^(11′) is —COOR (i.e., an ester) where the R group is asuitable protecting group.

[0404] Compounds E and F can be prepared from D as described in detailin Example 10 below.

[0405] Where R^(11′) is an ester containing a protecting group, thereaction conditions for removal of the protecting group will depend onthe type of the protecting group. For example, if the group is a2-cyanoethyloxy group, it is removed by treatment with piperidine or DBUin a halogenated organic solvent such as methylene chloride, followed bytreatment with an acid such as acetic acid to provide a compound offormula (I) where R^(11′) is carboxylic acid.

[0406] Compounds of Formula (I) where R¹ and R² are hydroxy, Z is agroup of formula —M—Q^(b)—D′ where M is —CH₂CH₂—C(O)—, Q^(b) is alinking group, and D′ is a GABA analog moiety related to formula (a)that is attached to Q^(b) through its terminal amino group can beprepared by methods well known in the art. Some such methods areillustrated and described below.

[0407] A compound of formula (I) wherein Q^(b) is a linking group offormula —O(CH(R^(a)))_(n)CO— where n=1-6 and R^(a) is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl can be preparedas shown below.

[0408] A compound of formula (I) wherein Q^(b) is a linking group offormula —O(CH(R^(a)))_(n)CO— where n=1-6 and R^(a) is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl can be preparedby first reacting a protected hydroxy acid of formula G (where Pg is aprotecting group) with compound A to provide a compound of formula H,which upon coupling with an amine of formula (a) then provides acompound of Formula (I). The coupling reactions are carried out underconditions well known in the art. A detailed description of thesynthesis of compounds of formula (I) utilizing the procedure describedabove is given in Working Examples 38-40 below. Hydroxy acids of formulaG include the a-hydroxy acids glycolic acid and lactic acid, theβ-hydroxy acid 3-hydroxyisobutyric acid, and are commercially availablein free and/or protected forms. Others can be prepared by methods wellknown in the art. It will be appreciated by a person skilled in the artthat amino acids such as serine, glutamic acid, aspartic acid can beused to 2prepare compounds of formula (I) wherein the linking groupcarries an acid moiety. Examples of such linking groups are—NH—CH(CO₂R^(b))—(CH₂)₂CO—, —NH—CH(CH₂OSO₃R^(b))—CO—, and the likewherein R^(b) is hydrogen or alkyl or an alkali cation. Detaileddescription of synthesis of compounds of formula (I) utilizing theselinking groups is provided in Examples 5 and 7.

[0409] Compounds of Formula (I) where R¹ and R² are hydroxy, X is agroup of formula D—Q^(a)—(T)— where T is —O—, Q^(a) is a cleavable bond,and D is a GABA analog moiety related to formula (a) that is attached toT through its carboxyl terminus can be prepared as illustrated anddescribed in Scheme C below.

[0410] A compound of Formula (I) where R¹ and R² are hydroxy, X is agroup of formula D—Q^(a)—(T)— where T is —O—, and D is a GABA analogmoiety related to formula (a) that is attached to T through its carboxylterminus can be prepared by reacting a compound of formula J (where R isa carboxyl protecting group) with a compound of formula (a) wherein R³is an amino protecting group and R¹¹ is —COL, wherein L is a suitableleaving group such as 2,4,6-trichlorobenzoyloxy to provide a compound offormula (I). The amino protecting group can be optionally removed toprovide a corresponding compound of formula (I) where R³ is hydrogen. Acompound of formula (I) can be converted to other compounds of formula(I). For example, the carboxy group at the C-24 carbon can be convertedto a —CONHCH₂—CH₂SO₃Na+ group by treating it with taurine as shown inFIG. 24 and described in Example 23 below.

[0411] Aditionally, FIGS. 11-33 and Working Examples 1-41 below describein detail synthesis of various other compound of formula (I).

[0412] Pharmaceutical Formulations

[0413] When employed as pharmaceuticals, the compounds of formulae(I)-(III) are usually administered in the form of pharmaceuticalcompositions that are administered by oral routes. Such compositions areprepared in a manner well known in the pharmaceutical art and compriseat least one active compound.

[0414] This invention also includes pharmaceutical compositions thatcontain, as the active ingredient one or more of the compounds offormulae (I)—(III) above associated with pharmaceutically acceptablecarriers. In making the compositions of this invention, the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,etc. containing, for example, up to 10% by weight of the active compoundusing, for example, soft and hard gelatin capsules.

[0415] In preparing a formulation, it may be necessary to mill theactive compound to provide the appropriate particle size prior tocombining with other ingredients. If the active compound issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g. ˜40 mesh.

[0416] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

[0417] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 0.1 to about 5000 mg, more usuallyabout 10 to about 2000 mg, of the active ingredient. The term “unitdosage forms” refers to physically discrete units suitable as unitarydosages for human subjects and other animals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

[0418] The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

[0419] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 mg to about 2 g of the activeingredient of the present invention.

[0420] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer that serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

[0421] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

[0422] The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

[0423] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning. Atm = atmosphere Boc = tert-butyloxycarbonylCbz = carbobenzyloxy CPM = counts per minute DIC =diisopropylcarbodiimide DMAP = 4-N,N-dimethylaminopyridine DMEM =Dulbecco's minimun eagle medium DMF = N,N-dimethylformamide DMSO =dimethylsulfoxide FMOC = 9-fluorenylmethyloxycarbonyl g = gram h = hourHBSS = Hank's buffered saline solution IBAT = intestinal bile acidtransporter L = liter LBAT = liver bile acid transporter LC/MS = liquidchromatography/mass spectroscopy M = molar min = minute mL = millilitermmol = millimols NTCP = Na+ taurocholate cotransporting polypeptide PBS= phosphate buffered saline PPTS = pyridinium p-toluenesulfonate TCBC =2,4,6-trichlorobenzoyl chloride THF = tetrahydrofuran TFA =trifluoroacetic acid TMSOTf = trimethylsilyltrifluoromethane- sulfonateTrisyl = 2,4,6-triispropylbenzenesulfonyl μL = microliter μM =micromolar v/v = volume to volume

Experimental Methods

[0424] The following examples illustrate how the synthesis ofdrug/linker/transporter conjugates could be conducted in order toprepare compounds of formula (I)-(III). The syntheses described beloware illustrated in FIGS. 11-33.

Example 1

[0425] Synthesis of Compound (8)

[0426] Cholic acid (6) (408 mg, 1 mmol) was dissolved in anhydrous THF(10 mL) and tributylamine (0.285 mL, 1.2 mmol) added slowly withstirring. The solution was cooled to −5° C. in an ice-salt bath, andethyl chloroformate (0.12 mL, 1.2 mmol) added slowly, maintaining thetemperature between −5 to 0° C. After addition was complete, the coldmixture was stirred for an additional 15 minutes. A solution containing1-aminomethyl-1-cyclohexaneacetic acid hydrochloride (Gabapentin, RBISigma) (2) (363 mg, 1.75 mmol) in 2N NaOH (3 mL) was added and themixture stirred for an additional 60 min at −5 to 0° C. After removal ofthe THF in vacuo, saturated NaHCO₃ (15 mL) was added and the aqueousmixture washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The product was extracted into EtOAc (3×15 mL), and thecombined organic phase dried over MgSO₄, and concentrated to dryness.The residue was purified by flash chromatography on silica gel (5%MeOH/CH₂Cl₂) to give pure free acid (7) (287 mg, 52% yield).Electrospray mass spectrometry showed the expected molecular ion atm/z=562.6 (M+H⁺). The corresponding sodium salt (8) was prepared inquantitative yield from (7) (287 mg, 0.52 mmol) by addition of amethanol solution of (7) to water containing 0.5N NaOH (1 eq.) andevaporation to dryness on a lyophilizer.

[0427] MS (ESI): m/z=560.6 (M−Na³¹).

[0428]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.34 (s,2H), 2.28 (s, 2H), 1.03 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.70 (s, 3H).

Example 2

[0429] Synthesis of Compound (10)

[0430] Pregabalin (3), prepared according the methods described inSilverman et al (U.S. Pat. No. 5,563,175), is transformed to the cholylamide (10) following the procedure detailed above for the gabapentinanalog (8).

[0431] MS (ESI): m/z 548.39 (M−H⁻), 550.41 (M+H⁺).

[0432]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 1.03 (d,3H, J=6.4 Hz), 0.91 (s, 3H), 0.83 (d, 3H, J=6.4 Hz), 0.81 (d, 3H, J=6.4Hz), 0.70 (s, 3H).

Example 3

[0433] Synthesis Compounds (13) and (14)

[0434] Cholic acid (6) (408 mg, 1 mmol) was dissolved in anhydrous THF(10 mL) and tributylamine (0.285 mL, 1.2 mmol) added slowly withstirring. The solution was cooled to −5° C. in an ice-salt bath, andethyl chloroformate (0.12 mL, 1.2 mmol) added slowly, maintaining thetemperature between −5 to 0° C. After addition was complete, the coldmixture was stirred for an additional 15 minutes. A solution containingeither glycine or phenylalanine (1.75 mmol) in 2N NaOH (2 mL) was addedand the mixture stirred for an additional 60 min at −5 to 0° C. Afterremoval of the THF in vacuo, saturated NaHCO₃ (15 mL) was added and theaqueous mixture washed with EtOAc (3×10 mi]L), then the pH adjusted to3-4 with citric acid. The product was extracted into EtOAc (3×15 mL),and the combined organic phase dried over MgSO₄, and concentrated todryness. The residue was purified by flash chromatography on silica gel(5% MeOH/CH₂Cl₂) to give pure free acids (11) and (12) (270 mg, 58%yield for (11)). Electrospray mass spectrometry showed the expectedmolecular ion at m/z=466.5 (for (11)) and 556.6 (for (12)) (M+H⁺). Theseadducts (0.2 mmol) were dissolved in anhydrous THF (5 mL) andtributylamine (0.22 mmol) added slowly with stirring. The solutions werecooled to −5° C. in an ice-salt bath, and ethyl chloroformate (22 μL,0.22 mmol) added slowly, maintaining the temperature between −5 to 0° C.After addition was complete, the cold mixtures were stirred for anadditional 15 minutes. A solution containing Gabapentin (2) (83 mg, 0.4mmol) in 2N NaOH (1.5 mL) was added and the mixtures stirred for anadditional 60 min at −5 to 0° C. After removal of the THF in vacuo,saturated NaHCO₃ (5 mL) was added and the aqueous mixtures washed withEtOAc (3×5 mL), then the pH adjusted to 3-4 with citric acid. Theproducts were extracted into EtOAc (3×10 mL), and the combined organicphases dried over MgSO₄, and concentrated to dryness. The residues werepurified by flash chromatography on silica gel (10% MeOH/CH₂Cl₂) to givepure free acids. The corresponding sodium salts (13) and (14) wereprepared in quantitative yield by addition of a methanol solution of theacids to water containing 0.5N NaOH (1 eq.) and evaporation to drynesson a lyophilizer.

[0435] Cholyl-Gly-Gabapentin (13): MS (ESI): m/z 617.50 (M−H⁻), 619.51(M+H⁺).

[0436]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.81 (s,2H), 3.34 (s, 2H), 2.28 (s, 2H), 1.03 (d, 3H, J=6.4 Hz), 0.91 (s, 3H),0.70 (s, 3H).

[0437] Cholyl-Phe-Gabapentin (14): MS (ESI): m/z 707.47 (M−H⁻), 709.36(M+H⁺).

[0438]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.26 (m,5H), 4.59 (m, 1H), 3.34 (s, 2H), 3.25-2.95 (m, 2H), 2.18 (d, 2H, J=7.2Hz), 0.98 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.68 (s, 3H).

Example 4

[0439] Synthesis of Compounds (15) and (16)

[0440] Pregabalin (3) is transformed to the cholylglycine andcholylphenylalanine adducts (15) and (16) following the proceduredetailed above for the gabapentin analogs (13) and (14).

[0441] Cholyl-Gly-Pregabalin (15): MS (ESI): m/z 605.57 (M−H⁻), 607.55(M+H⁺).

[0442]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.81 (s,2H), 1.03 (d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.83 (d, 3H, J=6.4 Hz), 0.81(d, 3H, J=6.4 Hz), 0.70 (s, 3H).

[0443] Cholyl-Gly-Pregabalin (16): MS (ESI): m/z 695.58 (M−H⁻), 697.53(M+H⁺).

[0444]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 7.25 (m,5H), 4.60 (m, 1H), 3.25-2.95 (m, 2H), 1.03 (d, 3H, J=6.4 Hz), 0.91 (s,3H), 0.83 (d, 3H, J=6.4 Hz), 0.81 (d, 3H, J=6.4 Hz), 0.70 (s, 3H).

Example 5

[0445] Synthesis of Compounds (23)-(26)

[0446] Cholic acid (6) (1 mmol) is dissolved in anhydrous THF (10 mL)and tributylamine (1.2 mmol) added slowly with stirring. The solution iscooled to −5° C. in an ice-salt bath, and ethyl chloroformate (1.2 mmol)added slowly, maintaining the temperature between −5 to 0° C. Afteraddition is complete, the cold mixture is stirred for an additional 15minutes. A solution containing the α-tert-butyl ester of either asparticacid or glutamic acid (1.75 mmol) in 2N NaOH (2 mL) is added and themixtures stirred for an additional 60 min at −5 to 0° C. After removalof the THF in vacuo, saturated NaHCO₃ (15 mL) is added and the aqueousmixtures washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The products are extracted into EtOAc (3×15 mL), and thecombined organic phases dried over MgSO₄, and concentrated to dryness.The residues are purified by flash chromatography on silica gel to givepure acids (17) and (18). These acids (0.4 mmol) are dissolved inanhydrous THF (10 mL) and tributylamine (0.45 mmol) added slowly withstirring. The solutions are cooled to −5° C. in an ice-salt bath, andethyl chloroformate (0.45 mmol) added slowly, maintaining thetemperature between −5 to 0° C. After addition is complete, the coldmixtures are stirred for an additional 15 minutes. A solution containingGabapentin (2) (0.7 mmol) in 2N NaOH (3 mL) is added and the mixturesstirred for an additional 60 min at −5 to 0° C. After removal of the THFin vacuo, saturated NaHCO₃ (10 mL) is added and the aqueous mixtureswashed with EtOAc (3×10 mL), then the pH adjusted to 3-4 with citricacid. The products are extracted into EtOAc (3×15 mL), and the combinedorganic phases dried over MgSO₄, and concentrated to dryness. Theresidues are purified by flash chromatography on silica gel to give purefree acids (19) and (20). The acids (0.15 mmol) are dissolved inmethanol (15 mL) and a freshly prepared solution of diazomethane indiethyl ether added until a pale yellow color persists. After stirringfor 60 min, the solvent is removed in vacuo to afford the methyl esterderivatives (21) and (22). The tert-butyl esters (19)-(22) aretransformed to the corresponding sodium salts (23)-(26) by firsttreating with 50% (v/v) TFA in CH₂Cl₂ for 30 min, purification of theresulting acids by flash chromatography on silica gel, and finallyaddition of methanolic solutions of the acids to water containing 0.5NNaOH (1 eq.) then evaporation to dryness on a lyophilizer.

Example 6

[0447] Synthesis of Compounds (30) and (31)

[0448] Cholic acid (6) (1 mmol) is dissolved in anhydrous THF (10 mL)and tributylamine (1.2 mmol) added slowly with stirring. The solution iscooled to −5° C. in an ice-salt bath, and ethyl chloroformate (1.2 mmol)added slowly, maintaining the temperature between −5 to 0° C. Afteraddition is complete, the cold mixture is stirred for an additional 15minutes. A solution containing the S-Trityl thioether derivative ofcysteine (1.5 mmol) and 2N NaOH (2 mL) in THF (15 mL) is added and themixture stirred for an additional 60 min at −5 to 0° C. After removal ofthe THF in vacuo, saturated NaHCO₃ (15 mL) is added and the aqueousmixture washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The product is extracted into EtOAc (3×15 mL), and thecombined organic phase dried over MgSO₄, and concentrated to dryness.The residue is purified by flash chromatography on silica gel to givepure acid (27). (27) (0.4 mmol) is dissolved in anhydrous THF (10 mL)and tributylamine (0.45 mmol) added slowly with stirring. The solutionis cooled to −5° C. in an ice-salt bath, and ethyl chloroformate (0.45mmol) added slowly, maintaining the temperature between −5 to 0° C.After addition is complete, the cold mixture is stirred for anadditional 15 minutes. A solution containing gabapentin (2) (0.7 mmol)in 2N NaOH (3 mL) is added and the mixture stirred for an additional 60min at −5 to 0° C. After removal of the THF in vacuo, saturated NaHCO₃(10 mL) is added and the aqueous mixture washed with EtOAc (3×10 mL),then the pH adjusted to 3-4 with citric acid. The product is extractedinto EtOAc (3×15 mL), and the combined organic phase dried over MgSO₄,and concentrated to dryness. The residue is purified by flashchromatography on silica gel to give gabapentin adduct (28). A portionof this product (0.15 mmol) is dissolved in MeOH (15 mL) and a freshlyprepared solution of diazomethane in diethyl ether added until a paleyellow color persists. After stirring for 60 min, the solvent is removedin vacuo to afford the methyl ester derivative (29). Compounds (28) and(29) (0.15 mmol) are treated with 50% (v/v) TFA in CH₂Cl₂ for 30 min andthe solvent removed in vacuo. The residues are dissolved in MeOH (15 mL)and vigorously stirred with an aqueous solution containing 30% (v/v)H₂O₂ and 2% H₂SO₄ (15 mL) for 48 h to oxidize the sulfhydryl moieties tosulfonic acids. The solvent is removed in vacuo and the residuespurified by flash chromatography on silica gel. Sodium salts of thegabapentin-cholyl cysteate conjugates (30) and (31) are prepared bydissolving each residue in 50% MeOH/H₂O (5 mL) and stirring with Na⁺cation exchange resin (prepared from Dowex HCR-W2, ˜1 mmol) for 30 min.The resins are washed with 50% MeOH/H₂O (3×5 mL) and the combinedfiltrates evaporated to dryness to afford compounds (30) and (31).

Example 7

[0449] Synthesis of Compound (35)

[0450] Cholic acid (6) (1 mmol) is dissolved in anhydrous THF (10 mL)and tributylamine (1.2 mmol) added slowly with stirring. The solution iscooled to −5° C. in an ice-salt bath, and ethyl chloroformate (1.2 mmol)added slowly, maintaining the temperature between −5 to 0° C. Afteraddition is complete, the cold mixture is stirred for an additional 15minutes. A solution containing the 0-tert-butyl ether derivative ofserine (1.5 mmol) and 2N NaOH (2 mL) in THF (10 mL) is added and themixture stirred for an additional 60 min at −5 to 0° C. After removal ofthe THF in vacuo, saturated NaHCO₃ (15 mL) is added and the aqueousmixture washed with EtOAc (3×10 mL), then the pH adjusted to 3-4 withcitric acid. The product is extracted into EtOAc (3×15 mL), and thecombined organic phase dried over MgSO₄, and concentrated to dryness.The residue is purified by flash chromatography on silica gel to givepure acid (32). (32) (0.4 mmol) is dissolved in anhydrous THF (10 mL)and tributylamine (0.45 mmol) added slowly with stirring. The solutionis cooled to −5° C. in an ice-salt bath, and ethyl chloroformate (0.45mmol) added slowly, maintaining the temperature between −5 to 0° C.After addition is complete, the cold mixture is stirred for anadditional 15 minutes. A solution containing gabapentin (2) (0.7 mmol)in 2N NaOH (3 mL) is added and the mixture stirred for an additional 60min at −5 to 0° C. After removal of the THF in vacuo, saturated NaHCO₃(10 mL) is added and the aqueous mixture washed with EtOAc (3×10 mL),then the pH adjusted to 3-4 with citric acid. The product is extractedinto EtOAc (3×15 mL), and the combined organic phase dried over MgSO₄,and concentrated to dryness. The residue is purified by flashchromatography on silica gel to give the cholylserine gabapentin acidadduct. This product is dissolved in MeOH (25 mL) and a freshly preparedsolution of diazomethane in diethyl ether added until a pale yellowcolor persists. After stirring for 60 min, the solvent is removed invacuo to afford the methyl ester derivative (33).

[0451] Compound (33) is peracetylated following literature methods(Opsenica et al, 2000). Briefly, (33) (0.5 mmol) is dissolved in asolution containing Ac₂O (1 mL) and TMSOTf (0.15 mmol) and stirred atroom temperature for 5 min. The reaction is quenched by addition ofsaturated NaHCO₃ (10 mL), the product is extracted into EtOAc (3×15 mL)and the combined organic phase dried over MgSO₄, and concentrated todryness. The residue is purified by flash chromatography on silica geland then treated with 50% (v/v) TFA in CH₂Cl₂ for 60 min to generatealcohol (34). Compound (34) (0.5 mmol) is dissolved in DMF (5 mL)containing py.SO₃ (0.55 mmol) and stirred for 4 h at room temperature.After removal of the solvent in vacuo, the residue is dissolved in dryMeOH (5 mL) and stirred with anhydrous K₂CO₃ (1.5 mmol) for 24 h and thesolvent again removed in vacuo. Dowex HCR-W2 ion exchange resin (H⁺form) is converted to the Na⁺ form by treatment with 1N NaOH for 30 min,followed by extensive washing with water till neutral. The crude sulfatecompound is dissolved in 50% MeOH/H₂O (10 mL) and the Na⁺ cationexchange resin (˜2 mmol) is added. The resulting mixture is shaken for30 min and filtered. The resin is washed with 50% MeOH/H₂O (3×10 mL) andthe combined filtrates evaporated to dryness to afford the sodium saltof 0-sulfate compound (35).

Example 8

[0452] Synthesis of Compound (39)

[0453] 1,1-Cyclohexanediacetic acid (4 g, 20 mmol) and acetic anhydride(3.8 mL, 40 mmol) were heated under reflux until a clear solution wasobtained (˜1 h), and heating continued for a further hour to ensure thereaction had gone to completion. The mixture was cooled to roomtemperature and the solvent removed in vacuo to afford1,1-cyclohexanediacetic anhydride (37) (3.6 g, 99% yield). Electrospraymass spectrometry showed the expected molecular ion at m/z=183.2 (M+H⁺).(37) (3.6 g 19.7 mmol) was stirred in 0.5M sodium methoxide/MeOHsolution (40 mL) at room temperature for 2 h. After removal of thesolvent in vacuo, 0.5 N HCl (20 mL) was added to the residue and theproduct extracted with EtOAc (3×30 mL). The combined organic phase wasdried over MgSO₄ and concentrated in vacuo to give monomethyl ester (38)(4 g, 95% yield). Electrospray mass spectrometry showed the expectedmolecular ion at m/z 213.3 (M−H⁻).

[0454] To a solution of (38) (1.6 g, 7.5 mmol) in anhydrous acetone (10mL) was slowly added triethylamine (1.25 mL, 9 mmol). The solution wascooled to −5 to 0° C. in an ice-salt bath and ethyl chloroformate (0.89mL, 9 mmol) in anhydrous acetone (10 mL) was added dropwise, maintainingthe temperature between −5 to 0° C. After addition was complete, thecold mixture was stirred for an additional 15 min. A solution of sodiumazide (975 mg, 15 mmol) in water (3 mL) was then added slowly, thetemperature being maintained between −5 to 0° C. The mixture was stirredfor an additional 30 min, poured into ice water (5 mL), and shaken withtoluene (4×25 mL). The combined toluene extracts were dried over MgSO₄and the resulting acyl azide (39) used immediately in a Curtius reactionwith the appropriate alcohol (vide infra).

Example 9

[0455] Synthesis of Compound (43)

[0456] Sodium hydride (252 mg, 10 mmol) was suspended in dry THF (100mL) under nitrogen and 3-hydroxypropylnitrile (40) (683 μL, 10 mmol)added slowly. The mixture was stirred at room temperature for 30 min,and then filtered under nitrogen to give a 0.1 M THF solution of sodium2-cyanoethoxide (41). This solution could be stored at −20° C. for lateruse.

[0457] (37) (1.82 g, 10 mmol) was treated with this 0.1 M sodium2-cyanoethoxide solution in THF (100 mL) for 2 hours at roomtemperature. After removal of the solvent in vacuo, the residue wastreated with saturated citric acid solution (20 mL) and the productextracted with EtOAc (3×30 mL). The combined organic phase was driedover MgSO₄, the solvent removed in vacuo, and the cyanoethyl esterproduct (42) (1.8 g, 71% yield) purified by flash chromatography onsilica gel (CH₂Cl₂—MeOH 97:3). Electrospray mass spectrometry showed theexpected molecular ion at m/z=276.3 (M+Na⁺).

[0458] To a solution of (42) (0.7 g, 2.8 mmol) in anhydrous acetone (5mL) was slowly added triethylamine (0.47 mL, 3.4 mmol). The solution wascooled to −5 to 0° C. in an ice-salt bath and ethyl chloroformate (0.34ML, 3.4 mmol) in anhydrous acetone (4 mL) was added dropwise,maintaining the temperature between −5 to 0° C. After addition wascomplete, the cold mixture was stirred for an additional 15 min. Asolution of sodium azide (440 mg, 6.8 mmol) in water (1 mL) was thenadded slowly, the temperature being maintained between −5 to 0° C. Themixture was stirred for an additional 30 min, poured into ice water (5mL), and shaken with toluene (4×10 mL). The combined toluene extractswere dried over MgSO₄ and the resulting acyl azide (43) used immediatelyin a Curtius reaction with the appropriate alcohol (vide infra).

Example 10

[0459] Synthesis of Compound (45)

[0460] 23-Nor−5β-cholanic acid-3α,7α,12α-triol (212) is prepared fromcholic acid according to the methods of Ayra and Burton (U.S. Pat. No.5,541,348). (212) (5 mmol) is stirred under nitrogen at room temperatureovernight in a solution containing pyridine (2 mL), acetic anhydride (10mL), DMAP (0.5 mmol) and CH₂Cl₂ (30 mL). The mixture is washed with asaturated aqueous solution of NH₄Cl, the organic layer dried over MgSO₄and the solvent removed in vacuo. A solution of the resultingtri-O-acetyl derivative (2 mmol) in CC14 (150 mL) containingiodosobenzene diacetate (1.1 mmol) and iodine (1 mmol) is irradiatedwith two 100-W tungsten-filament lamps at reflux temperature for 45 min.Additional portions of iodosobenzene diacetate (1.1 mmol) and iodine (1mmol) are added and irradiation continued at this temperature for 45min. The mixture is washed with dilute aqueous sodium thiosulfate andthe iodo-derivative (213) purified by flash chromatography on silicagel.

[0461] (213) (1 mmol) is heated at 40° C. in DMSO (5 mL) containingpotassium acetate (1.5 mmol) and 18-crown-6 (1 mmol) for 2 h. A solutionof 2N NaOH (2.5 mL) is added and stirring continued for an additional 4h. After removal of the solvent in vacuo, the residue is treated with asaturated aqueous solution of NH₄Cl and extracted with EtOAc (3×10 mL).The combined organic phase is dried over MgSO₄, the solvent removed invacuo, and the bis-norcholanol (214) purified by flash chromatography onsilica gel.

[0462] (214) (0.5 mmol) is heated under reflux in a toluene solutioncontaining acyl azide (43) (2 mmol) for 12 h. The solvent is removed invacuo, the residue dissolved in EtOAc (10 mL), washed with water (2×5mL) and dried over MgSO₄. After removal of the solvent in vacuo, thecyanoethyl ester product (44) is purified by preparative TLC on silicagel. (44) is treated with 20% (v/v) piperidine in CH₂Cl₂ (5 mL) for 30min and the solvent removed in vacuo. Aqueous citric acid (pH 3-4) isadded to the residue, the crude acid extracted with EtOAc (3×5 mL) andthe organic layer dried over MgSO₄. Purification by preparative TLC onsilica gel afforded gabapentin carbamate (45).

Example 11

[0463] Synthesis of Compound (47)

[0464] Cholic acid (6) (1 mmol) is dissolved in anhydrous THF (10 mL)and tributylamine (1.2 mmol) added slowly with stirring. The solution iscooled to −5° C. in an ice-salt bath, and ethyl chloroformate (1.2 mmol)added slowly, maintaining the temperature between −5 to 0° C. Afteraddition is complete, the cold mixture is stirred for an additional 15minutes. A solution containing the α-tert-butyl ester of serine (1.75mmol) in 2N NaOH (2 mL) is added and the mixture stirred for anadditional 60 min at −5 to 0° C. After removal of the THF in vacuo,saturated aqueous citric acid (pH ˜3) (15 mL) is added, the product isextracted into EtOAc (3×15 mL), and the combined organic phase driedover MgSO₄, and concentrated to dryness. The residue is purified byflash chromatography on silica gel to give cholylserine derivative (46).

[0465] (46) (0.5 mmol) is heated under reflux in a toluene solutioncontaining acyl azide (39) (2 mmol) for 12 h. The solvent is removed invacuo, the residue dissolved in EtOAc (10 mL), washed with water (2×5mL) and dried over MgSO₄. After removal of the solvent in vacuo, theresulting carbamate adduct is purified by preparative TLC on silica gel.This material is converted to the corresponding carboxylic acid (47) bytreatment with 50% (v/v) TFA in CH₂Cl₂ for 30 min followed bypreparative TLC on silica gel.

Example 12

[0466] Synthesis of Compound (52)

[0467] Phosphonoacetic acid ethyl ester (48) (10 mmol) is stirred indioxane (20 mL) with diispropylethylamine (DIEA, 20 mmol) and benzylbromide (20 mmol) for 4 h at room temperature. After removal of thesolvent in vacuo, product (49) is purified by flash chromatography onsilica gel. (49) (10 mmol) is dissolved in anhydrous THF (25 mL) andcooled to −78° C. A 0.5M toluene solution of potassiumhexamethyldisilazide (12 mmol) is added slowly followed by dropwiseaddition of a 2M THF solution of trisyl azide. After stirring for 2 h at−78° C., the solution is allowed to warm to room temperature and thesolvent is removed in vacuo. The resulting azidophosphonate is purifiedby flash chromatography on silica gel, dissolved in THF and treated withtriphenylphosphine (12 mmol) and water (12 mmol). After stirring for 8h, the solvent is removed in vacuo and the residue partitioned betweenCH₂Cl₂ and 0.5M aqueous KHSO₄ (pH=3-4). The organic layer is discardedand the aqueous phase basified to pH ˜9 with 0.5M Na₂CO₃. The crudeaminophosphonate (50) is isolated by extraction into EtOAc (3×20 mL),and after removal of the solvent in vacuo, used as is in the subsequentreaction.

[0468] Cholic acid (6) (1 mmol) is dissolved in anhydrous THF (10 mL)and tributylamine (1.2 mmol) added slowly with stirring. The solution iscooled to −5° C. in an ice-salt bath, and ethyl chloroformate (1.2 mmol)added slowly, maintaining the temperature between −5 to 0° C. Afteraddition is complete, the cold mixture is stirred for an additional 15minutes. A solution containing (50) (1.5 mmol) and pyridine (1 mL) inTHF (5 mL) is added and the mixture stirred for an additional 60 min at−5 to 0° C. After removal of the solvent in vacuo, saturated aqueouscitric acid (pH ˜3) (15 mL) is added, the product is extracted intoEtOAc (3×15 mL), and the combined organic phase dried over MgSO₄, andconcentrated to dryness. The residue is dissolved in EtOH (10 mL) andsodium borohydride (1.5 mmol) added with stirring. After warming thesolution to 40° C. for 2 h, the solvent is removed in vacuo and theresidue purified by flash chromatography on silica gel to afford alcohol(51).

[0469] (51) (0.5 mmol) is heated under reflux in a toluene solutioncontaining acyl azide (39) (2 mmol) for 12 h. The solvent is removed invacuo, the residue dissolved in EtOAc (10 mL), washed with water (2×5mL) and dried over MgSO₄. After removal of the solvent in vacuo, theresulting carbamate adduct is purified by preparative TLC on silica gel.This material is converted to the sodium salt of the correspondingcarboxylic acid, (52), by hydrogenation over 5% palladium on charcoal (8h in EtOAc/HOAc), removal of the solvent in vacuo, and dissolution ofthe residue in 50% MeOH/H₂O (5 mL) and stirring with Na⁺ cation exchangeresin (prepared from Dowex HCR-W2, ˜2 mmol) for 30 min. The resin iswashed with 50% MeOH/H₂O (3×5 mL) and the combined filtrates evaporatedto dryness to afford compound (52).

Example 13

[0470] Synthesis of Compound (55)

[0471] (27) (1 mmol) is dissolved in anhydrous THF (10 mL) andtributylamine (1.2 mmol) added slowly with stirring. The solution iscooled to −5° C. in an ice-salt bath, and ethyl chloroformate (1.2 mmol)added slowly, maintaining the temperature between −5 to 0° C. Afteraddition is complete, the cold mixture is stirred for an additional 15minutes then a solution of sodium borohydride (1.5 mmol) in EtOH (5 mL)added and the mixture stirred at room temperature for 2 h. After removalof the solvent in vacuo, the residue is purified by flash chromatographyon silica gel to afford alcohol (54).

[0472] (54) (0.5 mmol) is heated under reflux in a toluene solutioncontaining acyl azide (39) (2 mmol) for 12 h. The solvent is removed invacuo, the residue dissolved in EtOAc (10 mL), washed with water (2×5mL) and dried over MgSO₄. After removal of the solvent in vacuo, theresulting carbamate adduct is purified by preparative TLC on silica gel.This material is converted to the corresponding carboxylic acid bytreatment with 50% (v/v) TFA in CH₂Cl₂ for 30 min and the solvent isremoved in vacuo. The residue is dissolved in MeOH (5 mL) and vigorouslystirred with an aqueous solution containing 30% (v/v) H₂O₂ and 2% H₂SO₄(5 mL) for 48 h to oxidize the sulfhydryl moiety to the sulfonic acid.The solvent is removed in vacuo and the residue purified by flashchromatography on silica gel. The sodium salt (55) is prepared bydissolution of the sulfonic acid in 50% MeOH/H₂O (5 mL) and stirringwith Na⁺ cation exchange resin (prepared from Dowex HCR-W2, ˜2 mmol) for30 min. The resin is washed with 50% MeOH/H₂O (3×5 mL) and the combinedfiltrates evaporated to dryness to afford compound (55).

Example 14

[0473] Synthesis of Compounds (60) and (61)

[0474] A suspension of mercuric oxide (5 mmol) and cholic acid (6) (10mmol) in CH₂Cl₂ (75 mL) is stirred overnight at room temperature. 10mmol of either chloromethyl 4-nitrophenyl carbonate (56) (Maybridge) or2-chloro-isopropyl 4-nitrophenyl carbonate (57) (prepared as describedby Alexander, U.S. Pat. No. 5,684,018) is added to this suspension andstirring continued for 24 h. The solutions are washed with saturatedNaHCO₃, water and brine and the organic phase evaporated to dryness. Theresidues are purified by flash chromatography on silica gel to affordcarbonates (58) and (59) respectively.

[0475] (58) or (59) (1 mmol each) is dissolved in dioxane (10 mL) and asolution of gabapentin (2) (1 mmol) in aqueous phosphate buffer at pH˜8.5 (1 mL) added with vigorous stirring. After 2 h, the solvent isremoved in vacuo, the residues treated with aqueous citric acid (pH 3-4)and extracted with EtOAc (3×10 mL). The combined organic phases aredried over MgSO₄, concentrated to ˜5 mL and purified by flashchromatography on silica gel. Neutralization of the gabapentinacyloxyalkylcarbamates with 0.5N NaOH afforded sodium salts (60) and(61).

Example 15

[0476] Synthesis of Compounds (74)—(81)

[0477] A suspension of mercuric oxide (1 mmol) and either (17) or (18)(2 mmol) in CH₂Cl₂ (15 mL) is stirred overnight at room temperature. 2mmol of either (56) or (57) is added to these suspensions and stirringcontinued for 24 h. The four solutions are washed with saturated NaHCO₃,water and brine and the organic phase evaporated to dryness. Theresidues are purified by flash chromatography on silica gel to affordcarbonates (62)-(65). (62)-(65) (1 mmol each) are dissolved in dioxane(10 mL) and a solution of gabapentin (2) (1 mmol) in aqueous phosphatebuffer at pH ˜8.5 (1 mL) added with vigorous stirring. After 2 h, thesolvent is removed in vacuo, the residues treated with aqueous citricacid (pH 3-4) and extracted with EtOAc (3×10 mL). The combined organicphases are dried over MgSO₄, concentrated to ˜5 mL and purified by flashchromatography on silica gel to afford the acids (66)-(69).

[0478] (66)-(69) (1 mmol each) are dissolved in methanol (15 mL) and afreshly prepared solution of diazomethane in diethyl ether added until apale yellow color persists. After stirring for 60 min, the solvent isremoved in vacuo to afford the methyl ester derivatives (70)-(73).(66)-(73) (1 mmol each) are treated with 50% (v/v) TFA in CH₂Cl₂ for 30min and the solvent removed in vacuo. The acids are converted to thecorresponding sodium salts by dissolving each residue in 50% MeOH/H₂O (5mL) and stirring with Na⁺ cation exchange resin (prepared from DowexHCR-W2, ˜2 mmol) for 30 min. The resins are washed with 50% MeOH/H₂O(3×5 mL) and the combined filtrates evaporated to dryness to afford(74)-(81).

Example 16

[0479] Synthesis of Compounds (88)—(91)

[0480] A suspension of mercuric oxide (1 mmol) and (27) (2 mmol) inCH₂Cl₂ (15 mL) is stirred overnight at room temperature. 2 mmol ofeither (56) or (57) is added to this suspension and stirring continuedfor 24 h. The solutions are washed with saturated NaHCO₃, water andbrine and the organic phase evaporated to dryness. The residues arepurified by flash chromatography on silica gel to afford carbonates (82)and (83). (82) and (83) (1 mmol each) are dissolved in dioxane (10 mL)and a solution of gabapentin (2) (1 mmol) in aqueous phosphate buffer atpH ˜8.5 (1 mL) added with vigorous stirring. After 2 h, the solvent isremoved in vacuo, the residues treated with aqueous citric acid (pH 3-4)and extracted with EtOAc (3×10 mL). The combined organic phases aredried over MgSO₄, concentrated to ˜5 mL and purified by flashchromatography on silica gel to afford the acids (84) and (85).

[0481] (84) and (85) (1 mmol each) are dissolved in methanol (15 mL) anda freshly prepared solution of diazomethane in diethyl ether added untila pale yellow color persists. After stirring for 60 min, the solvent isremoved in vacuo to afford the methyl ester derivatives (86) and (87).

[0482] (84)-(87) (1 mmol each) are treated with 50% (v/v) TFA in CH₂Cl₂for 30 min and the solvent removed in vacuo. The residues are dissolvedin MeOH (5 mL) and vigorously stirred with an aqueous solutioncontaining 30% (v/v) H₂O₂ and 2% H₂SO₄ (5 mL) for 48 h to oxidize thesulfhydryl moieties to sulfonic acids. The solvent is removed in vacuoand the residues purified by flash chromatography on silica gel. Theacids are converted to the corresponding sodium salts by dissolving eachcompound in 50% MeOH/H₂O (5 mL) and stirring with Na⁺ cation exchangeresin (prepared from Dowex HCR-W2, ˜2 mmol) for 30 min. The resins arewashed with 50% MeOH/H₂O (3×5 mL) and the combined filtrates evaporatedto dryness to afford (88)-(91).

Example 17

[0483] Synthesis of Compounds (92)-(103)

[0484] Compounds (92)-(103) are prepared following methods described inU.S. Provisional Patent Application Serial No. 60/238,758 of Gallop andCundy entitled “Bile Acid—Derived Compounds for Enhancing OralAbsorption and Systemic Bioavailability of Drugs” filed on Oct. 6, 2000which application is incorporated herein by reference in its entirety.

Example 18

[0485] Synthesis of Compound (104)

[0486] A solution of di-tert-butyl carbonate (10 mmol) in dioxane (5 mL)is added to a solution containing gabapentin (2) (10 mmol) and potassiumcarbonate (5 mmol) in 75% (v/v) dioxane/water (5 mL) cooled to 5° C.After stirring for 2 h, the solvent is removed in vacuo and the residuepartitioned between aqueous citric acid (pH 3) and EtOAc. The organicphase is dried over MgSO₄, and evaporated to dryness yieldingBoc-protected gabapentin (104).

Example 19

[0487] Synthesis of Compound (105)

[0488] A solution of ethyl chloroformate (10 mmol) in dioxane (5 mL) isadded to a solution containing gabapentin (2) (10 mmol) and potassiumcarbonate (5 mmol) in dioxane (5 mL) cooled to 5° C. After stirring for2 h, the solvent is removed in vacuo and the residue partitioned betweenaqueous citric acid (pH 3) and EtOAc. The organic phase is dried overMgSO₄, and evaporated to dryness yielding ethyl carbamate (105).

Example 20

[0489] Synthesis of Compound (108)

[0490] A solution containing ethyl 6-hydroxyhexanoate (106) (162 μL, 1mmol), 3,4-dihydro-2H-pyran (137 μL, 1.5 mmol) and pyridiump-toluenesulfonate (25 mg, 0.1 mmol) in dry CH₂Cl₂ (10 mL) was stirredat room temperature for 4 h. CH₂Cl₂ (10 mL) was added and the reactionmixture and washed with brine (3×5 mL). The organic phase was dried overMgSO₄ and evaporated to dryness yielding (107). The resulting residuewas treated with aqueous 0.5 N NaOH (10 mL) and MeOH (10 mL) at 60° C.for 2 h. After removal of MeOH in vacuo and washing with CH₂Cl₂ (10 mL),the aqueous phase was acidified with citric acid. Extraction with ether(3×15 mL) and concentration in vacuo gave the THP-protected hydroxy-acid(108) (216 mg, 100% yield), which was used without further purification.Electrospray mass spectrometry showed the expected molecular ion atm/z=215.3 (M−H⁻).

Example 21

[0491] Synthesis of Compound (109)

[0492] To a solution of cholic acid (6) (2.04 g, 5 mmol) in dry THF (100mL) was added triethylamine (765 μL, 5.5 mmol) followed by2,4,6-trichlorobenzoylchloride (858 μL, 5.5 mmol). After 10 min asolution of 3-hydroxypropylnitrile (40) (341 μL, 5 mmol) in dry THF wasadded followed by DMAP (65 mg). The mixture was stirred at roomtemperature for 18 h. The reaction mixture was washed with saturatedNaHCO₃ (10 mL) then saturated aqueous citric acid (3×10mL). The organicphase was dried over MgSO₄, the solvent removed in vacuo and the residuepurified by flash chromatography on silica gel (CH₂Cl₂—MeOH 97:3) togive pure cyanoethyl cholate (109) (2.05 g, 89% yield).

[0493] MS (ESI): m/z=462.6 (M+H⁺).

[0494]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.27 (t,2H, J=6 Hz), 2.70 (t, 2H, J=6 Hz), 0.99 (d, 3H, J=6.4 Hz), 0.88 (s, 3H),0.68 (s, 3H).

Example 22

[0495] Synthesis of Compounds (112) and (113)

[0496] To a solution of (105) (1 mmol) in dry THF (10 mL) is addedtriethylamine (1.1 mmol) followed by 2,4,6-trichlorobenzoylchloride (1.1mmol). After 10 min a solution of either (92) or (93) (1 mmol each) indry THF (5 mL) is added followed by DMAP (0.5 mmol). The mixture isstirred at room temperature for 18 h. The reaction mixture is washedwith saturated NaHCO₃ (10 mL) then saturated aqueous citric acid (3×10mL). The organic phase is dried over MgSO₄, the solvent removed in vacuoand the residue purified by flash chromatography on silica gel to giverespectively the 3α- and 3β-tert-butyl cholate derivatives. These aretreated with 50% (v/v) TFA in CH₂Cl₂ for 30 min and the solvent removedin vacuo to afford (110) and (111).

[0497] (110) and (111) (1 mmol) are each dissolved in dry dioxane (10mL) containing tri-n-butylamine (2 mmol), cooled to 0° C., and ethylchloroformate (1 mmol) added dropwise. After stirring for 20 min asolution of taurine (2 mmol) in 2 M aqueous NaOH (1 mL) is slowly addedand the mixtures warmed to room temperature with stirring for 2 h. Themixtures are poured into water (20 mL), neutralized with IM aqueous HCl,and extracted thoroughly with ethyl acetate containing 5% (v/v)methanol. The organic layers are dried over MgSO₄ and chromatographed onsilica gel to afford the corresponding taurocholate conjugates. Thesesulfonic acids are converted to the corresponding sodium salts bydissolving each compound in 50% MeOH/H₂O (5 mL) and stirring with Na⁺cation exchange resin (prepared from Dowex HCR-W2, ˜4 mmol) for 30 min.The resins are washed with 50% MeOH/H₂O (3×5 mL) and the combinedfiltrates evaporated to dryness to afford (112) and (113).

Example 23

[0498] Synthesis of Compounds (114) and (115)

[0499] To a solution of (105) (1 mmol) in dry THF (10 mL) is addedtriethylamine (1.1 mmol) followed by 2,4,6-trichlorobenzoylchloride (1.1mmol). After 10 min a solution of either (96) or (97) (1 mmol each) indry THF (5 mL) is added followed by DMAP (0.5 mmol). The mixtures arestirred at room temperature for 18 h then washed with saturated NaHCO₃(10 mL) and saturated aqueous citric acid (3×10 mL). The organic layersare dried over MgSO₄, the solvent removed in vacuo and the residuespurified by flash chromatography on silica gel to give respectively the3α- and 3β-glycocholate tert-butyl ester derivatives. These compoundsare treated with 50% (v/v) TFA in CH₂Cl₂ for 30 min and the solventremoved in vacuo. The acids are converted to the corresponding sodiumsalts by dissolving each compound in 50% MeOH/H₂O (5 mL) and stirringwith Na⁺ cation exchange resin (prepared from Dowex HCR-W2, ˜4 mmol) for30 min. The resins are washed with 50% MeOH/H₂O (3×5 mL) and thecombined filtrates evaporated to dryness to afford (114) and (115).

Example 24

[0500] Synthesis of Compound (116)

[0501] CBz-phenylalanine (2 mmol) is dissolved in anhydrous dioxane (10mL) and tributylamine (2.5 mmol) added slowly with stirring. Thesolution is cooled to −5° C. in an ice-salt bath, and ethylchloroformate (2.5 mmol) added slowly, maintaining the temperaturebetween −5 to 0° C. After addition is complete, the cold mixture isstirred for an additional 15 minutes. A solution containing gabapentin(2) (3 mmol) in 2N NaOH (2 mL) is added and the mixture stirred for anadditional 60 min at 0° C. After removal of the dioxane in vacuo,saturated NaHCO₃ (15 mL) is added and the aqueous mixture washed withEtOAc (3×10 mL), then the pH adjusted to 3-4 with citric acid. Theproduct is extracted into EtOAc (3×15 mL), and the combined organicphases dried over MgSO₄, and concentrated to dryness. Purification byflash chromatography on silica gel afforded peptide (116).

Example 25

[0502] Synthesis of Compounds (119) and (120)

[0503] To a solution of (116) (1 mmol) in dry THF (10 mL) is addedtriethylamine (1.1 mmol) followed by 2,4,6-trichlorobenzoylchloride (1.1mmol). After 10 min a solution of either (92) or (93) (1 mmol each) indry THF (5 mL) is added followed by DMAP (0.5 mmol). The mixture isstirred at room temperature for 18 h. The reaction mixture is washedwith saturated NaHCO₃ (10 mL) then saturated aqueous citric acid (3×10mL). The organic phase is dried over MgSO₄, the solvent removed in vacuoand the residue purified by flash chromatography on silica gel to giverespectively the 3α- and 3β-tert-butyl cholate derivatives. These aretreated with 50% (v/v) TFA in CH₂Cl₂ for 30 min and the solvent removedin vacuo to afford (117) and (118).

[0504] (117) and (118) (1 mmol) are each dissolved in dry dioxane (10mL) containing tri-n-butylamine (2 mmol), cooled to 0° C., and ethylchloroformate (1 mmol) added dropwise. After stirring for 20 min asolution of taurine (2 mmol) in 2 M aqueous NaOH (1 mL) is slowly addedand the mixtures warmed to room temperature with stirring for 2 h. Themixtures are poured into water (20 mL), neutralized with 1M aqueous HCl,and extracted thoroughly with ethyl acetate containing 5% (v/v)methanol. The organic layers are dried over MgSO₄ and chromatographed onsilica gel to afford the corresponding taurocholate conjugates. Thesesulfonic acids are converted to the corresponding sodium salts bydissolving each compound in 50% MeOH/H₂O (5 mL) and stirring with Na⁺cation exchange resin (prepared from Dowex HCR-W2, ˜4 mmol) for 30 min.The resins are washed with 50% MeOH/H₂O (3×5 mL) and the combinedfiltrates evaporated to dryness. The salts are each dissolved in 10%aqueous EtOH (5 mL) and stirred with 5% Pd/C (50 mg) under 1 atmhydrogen gas for 2 h, affording the pure Phe-gabapentin conjugates (119)and (120).

Example 26

[0505] Synthesis of Compounds (121) and (122)

[0506] To a solution of (116) (1 mmol) in dry THF (10 mL) is addedtriethylamine (1.1 mmol) followed by 2,4,6-trichlorobenzoylchloride (1.1 mmol). After 10 min a solution of either (96) or (97) (1 mmol each) indry THF (5 mL) is added followed by DMAP (0.5 mmol). The mixtures arestirred at room temperature for 18 h then washed with saturated NaHCO₃(10 mL) and saturated aqueous citric acid (3×10 mL). The organic layersare dried over MgSO₄, the solvent removed in vacuo and the residuespurified by flash chromatography on silica gel to give respectively the3α- and 3β-glycocholate tert-butyl ester derivatives. These compoundsare treated with 50% (v/v) TFA in CH₂Cl₂ for 30 min and the solventremoved in vacuo. The acids are converted to the corresponding sodiumsalts by dissolving each compound in 50% MeOH/H₂O (5 mL) and stirringwith Na⁺ cation exchange resin (prepared from Dowex HCR-W2, ˜4 mmol) for30 min. The resins are washed with 50% MeOH/H₂O (3×5 mL) and thecombined filtrates evaporated to dryness. The salts are each dissolvedin 10% aqueous EtOH (5 mL) and stirred with 5% Pd/C (50 mg) under 1 atmhydrogen gas for 2 h, affording the pure Phe-gabapentin conjugates (121)and (122).

Example 27

[0507] Synthesis of Compound (124)

[0508] To a solution of (108) (216 mg, 1 mmol) in dry CH₂Cl₂ (10 mL) wasadded triethylamine (167 μL, 1.2 mmol) followed by2,4,6-trichlorobenzoylchloride (187 μL, 1.2 mmol). After 10 min, asolution of (96) (521 mg, 1 mmol) in dry CH₂Cl₂ (20 mL) was addeddropwise, followed by DMAP (12 mg). The reaction mixture was stirred atroom temperature for 18 h, then washed with saturated aqueous NaHCO₃ (10mL) and saturated aqueous citric acid (3×10 mL). The organic phase wasdried over MgSO₄ and purified by flash chromatography on silica gel(CH₂Cl₂—MeOH 97:3) to give compound (123) (345 mg, 48% yield).

[0509] MS (ESI): m/z=742.6 (M+Na⁺).

[0510]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.91 (s,2H), 1.44 (s, 9H), 0.97 (d, 3H, J=6.4 Hz), 0.88 (s, 3H), 0.67 (s, 3H).

[0511] A mixture of (123) (230 mg, 0.32 mmol) and pyridiump-toluenesulfonate (8 mg, 0.032 mmol) in MeOH (10 mL) was stirred at 55°C. for 4 h. The solvent was removed in vacuo, and the residue purifiedby chromatography on silica gel to afford the pure alcohol intermediate(173 mg, 85% yield). Electrospray mass spectrometry showed the expectedmolecular ion at m/z=636.6 (M+H⁺). A sample of this product (48 mg,0.075 mmol) was heated under reflux with a toluene solution containingacyl azide (39) (˜2.5 mmol) for 14 h. After cooling to room temperature,the solvent was removed in vacuo and the residue dissolved in EtOAc (20mL), washed with water (2×10 mL) and dried over MgSO₄. This tent-butylester product (30 mg, 47% yield) was purified using preparative TLC (10%MeOH/CH₂Cl₂). Electrospray mass spectrometry showed the expectedmolecular ion at m/z=847.63 (M+H⁺). The ester was treated with 50%TFA/CH₂Cl₂ for 3 h, the solvent removed in vacuo and the resultingresidue stirred for 30 min with 20% piperidine in CH₂Cl₂ (10 mL). Afterremoval of the solvent in vacuo, the residue was purified usingpreparative TLC (10% MeOH/CH₂Cl₂) to afford glycocholate derivative(124) (15 mg, 54% yield).

[0512] MS (ESI): 791.6 (M+H⁺).

[0513]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.88 (s,2H), 3.65 (s, 3H), 3.34 (s, 2H), 2.28 (s, 2H), 1.02 (d, 3H, J=6.4 Hz),0.91(s, 3H), 0.71 (s, 3H).

Example 28

[0514] Synthesis of Compound (125)

[0515] (109) (120 mg, 0.26 mmol) was heated under reflux with a toluenesolution containing acyl azide (39) (˜2.5 mmol) for 14 h. After coolingto room temperature, the solvent was removed in vacuo and the residuedissolved in EtOAc (20 mL), washed with water (2×10 mL) and dried overMgSO₄. The cyanoethyl ester product (40 mg, 23% yield) was purifiedusing preparative TLC (10% MeOH/CH₂Cl₂). Electrospray mass spectrometryshowed the expected molecular ion at m/z=673.5 (M+H⁺). This material wastreated with 20% piperidine/CH₂Cl₂ (2 mL) for 30 min and the solventremoved in vacuo. Purification of the resulting residue by preparativeTLC (10% MeOH/CH₂Cl₂) afforded the gabapentin carbamate conjugate (125)(28 mg, 77% yield). Electrospray mass spectrometry showed the expectedmolecular ion at m/z=620.6 (M+H⁺).

Example 29

[0516] Synthesis of Compound (126)

[0517] (125) (0.5 mmol) is dissolved in dry dioxane (5 ML) containingtri-n-butylamine (1 mmol), cooled to 0° C., and ethyl chloroformate (0.5mmol) added dropwise. After stirring for 20 min a solution of taurine (1mmol) in 2 M aqueous NaOH (0.5 mL) is slowly added and the mixturewarmed to room temperature with stirring for 2 h. The mixture is pouredinto water (10 mL), neutralized with 1M aqueous HCl, and extractedthoroughly with ethyl acetate containing 5% (v/v) methanol. The organiclayer is dried over MgSO₄ and chromatographed on silica gel to affordthe corresponding taurocholate conjugate. This sulfonic acid isconverted to the corresponding sodium salt by dissolution in 50%MeOH/H₂O (2 mL) and stirring with Na⁺ cation exchange resin (preparedfrom Dowex HCR-W2, ˜2 mmol) for 30 min. The resin is washed with 50%MeOH/H₂O (3×2 mL) and the combined filtrates evaporated to dryness toafford compound (126).

Example 30

[0518] Synthesis of Compounds (127)-(130)

[0519] (102) and (103) (0.5 mmol each) are separately heated underreflux with a toluene solution containing either acyl azide (39) or (43)(˜2.5 mmol) for 14 h. After cooling to room temperature, the solvent isremoved in vacuo and the four residues dissolved in EtOAc (20 mL),washed with water (2×10 mL) and dried over MgSO₄. The products arepurified by preparative TLC on silica gel plates. The two cyanoethylester products are deprotected by treatment with 20% piperidine/CH₂Cl₂(2 mL) for 30 min and the solvent removed in vacuo. The four tert-butylesters are treated with 50% (v/v) TFA in CH₂Cl₂ for 30 min and thesolvent removed in vacuo. The acids are converted to the correspondingsodium salts by dissolving each compound in 50% MeOH/H₂O (5 mL) andstirring with Na⁺ cation exchange resin (prepared from Dowex HCR-W2, ˜2mmol) for 30 min. The resins are washed with 50% MeOH/H₂O (3×5 mL) andthe combined filtrates evaporated to dryness to afford compounds(127)-(130).

Example 31

[0520] Synthesis of Compounds (139)-(146)

[0521] Compounds (131)-(134) are prepared from compounds (96)-(99)respectively following the method of Batta et al (J. Lipid Res. 1991,32, 977-983). The starting steroids (5 mmol) are heated under reflux ina mixture of carbon tetrachloride (10 mL) and pyridine (10 mL) withsuccinic anhydride (5 mmol) for 3 h. The solvent is removed in vacuo andthe residues taken up in ethyl acetate, washed with 0.2 M aqueous KHSO₄,dried over MgSO₄ then chromatographed on silica gel to give thehemisuccinate products (131)-(134).

[0522] These acids (2 mmol each) are separately dissolved in anhydrousdioxane (20 mL) and tributylamine (2.2 mmol) added slowly with stirring.The solutions are cooled to −5° C. in an ice-salt bath, and ethylchloroformate (2.2 mmol) added slowly, maintaining the temperaturebetween −5 to 0° C. After addition is complete, the cold mixtures arestirred for an additional 15 minutes. A solution containing gabapentin(2) (3 mmol) in 2N NaOH (3 mL) is added and the mixtures stirred for anadditional 60 min at −5 to 0° C. After removal of the dioxane in vacuo,saturated NaHCO₃ (20 mL) is added and the aqueous mixtures washed withEtOAc (3×10 mL), then the pH adjusted to 3-4 with citric acid. Theproducts are extracted into EtOAc (3×20 mL), and the combined organicphases dried over MgSO₄, and concentrated to dryness. The residues arepurified by flash chromatography on silica gel to give the gabapentinacid conjugates acids (135)-(138).

[0523] These acids (135)-(138) (0.5 mmol each) are separately dissolvedin methanol (10 mL) and a freshly prepared solutions of diazomethane indiethyl ether added until a pale yellow color persists. After stirringfor 60 min, the solvent is removed in vacuo to afford the correspondingmethyl ester derivatives.

[0524] The tert-butyl ester moieties in acids (135)-(138) and theircorresponding methyl ester analogs (0.5 mmol each) are transformed tothe corresponding sodium salts (139)-(146) by first treating with 50%(v/v) TFA in CH₂Cl₂ (5 mL) for 30 min, purification of the resultingacids by flash chromatography on silica gel, and finally stirring eachcompound in 50% MeOH/H₂O (5 mL) with Na⁺ cation exchange resin (preparedfrom Dowex HCR-W2, ˜2 mmol) for 30 min.

Example 32

[0525] Synthesis of Compounds (143)-(158)

[0526] A suspension of mercuric oxide (1 mmol) and each of (131)-(134)(2 mmol) in CH₂Cl₂ (15 mL) are separately stirred overnight at roomtemperature. 2 mmol of either (56) or (57) is added to these suspensionsand stirring continued for 24 h. The eight solutions are washed withsaturated NaHCO₃, water and brine and the organic phase evaporated todryness. The residues are purified by flash chromatography on silica gelto afford carbonates (135)-(142).

[0527] (135)-(142) (1 mmol each) are dissolved in dioxane (10 mL) and asolution of gabapentin (2) (1 mmol) in aqueous phosphate buffer at pH˜8.5 (1 mL) added to each with vigorous stirring. After 2 h, the solventis removed in vacuo, the residues treated with aqueous citric acid (pH3-4) and extracted with EtOAc (3×10 mL). The combined organic phases aredried over MgSO₄, concentrated to ˜5 mL and purified by flashchromatography on silica gel to afford the corresponding gabapentin acidadducts. Each adduct is divided into two equal portions, one of which isdissolved in methanol (5 mL) and stirred with excess of a freshlyprepared solution of diazomethane in diethyl ether. After stirring for60 min, the solvent is removed in vacuo to afford the methyl esteranalogs. These esters along with the remaining portions of their acidprecursors are separately treated with 50% (v/v) TFA in CH₂Cl₂ for 30min and the solvent removed in vacuo. The products are converted to thecorresponding sodium salts by dissolving each residue in 50% MeOH/H₂O (5mL) and stirring with Na⁺ cation exchange resin (prepared from DowexHCR-W2, ˜4 mmol) for 30 min. The resins are washed with 50% MeOH/H₂O(3×5 mL) and the combined filtrates evaporated to dryness to affordcompounds (143)-(158).

Example 33

[0528] Synthesis of Compounds (163)-(166)

[0529] Four solutions containing Fmoc-phenylalanine (1 mmol) and one ofcompounds (96)-(99) (1 mmol each) in dry DMF (4 mL) are treated withdiisopropylcarbodiimide (DIC) (1 mmol) for 4 h at room temperature.After filtering the solutions, the solvent is removed in vacuo, theresidues redissolved in ethyl acetate and washed thoroughly with 0.2 Maqueous solutions of KHSO₄. The organic layers are dried over MgSO₄ andchromatographed on silica gel to afford compounds (159)-(162).

[0530] Each product is stirred for 30 min in a 20% (v/v) solution ofpiperidine in DMF (5 mL) and the solvent removed in vacuo. To eachresidue is added a solution containing (104) (1.2 mmol) and DIC (1.2mmol) in DMF (5 mL) and the mixtures stirred at room temperature for 2h. After filtering the solutions, the solvent is removed in vacuo, theresidues are redissolved in ethyl acetate and washed thoroughly withsaturated aqueous NaHCO₃. The organic layers are dried over MgSO₄ andchromatographed on silica gel to afford the protected gabapentinpeptidyl glycocholates. These products are separately treated with 50%(v/v) TFA in CH₂Cl₂ for 30 min and the solvent removed in vacuo toafford compounds (163)-(166).

Example 34

[0531] Synthesis of Compound (167)

[0532] Compound (116) (1 mmol) dissolved in EtOH (20 mL) is stirred with5% Pd/C (100 mg) under 1 atm hydrogen gas for 2 h and the solventremoved in vacuo to afford compound (167) in quantitative yield.

Example 35

[0533] Synthesis of Compounds (168)-(175)

[0534] Solutions of compounds (96)-(99) (1 mmol each) in dry CH₂Cl₂ (10mL) and pyridine (1 mL) are cooled to 0° C. and separately treated with4-nitrophenyl chloroformate (1 mmol) with stirring for 2 h. Thesolutions are washed with saturated NaHCO₃, water and brine and theorganic layers evaporated to dryness. The residues are purified by flashchromatography on silica gel to afford the intermediate 4-nitrophenylcarbonates or carbamates. Each product is separately dissolved indioxane (5 mL) and a solution of (167) (1 mmol) in aqueous phosphatebuffer at pH ˜8.5 (1 mL) added to each with vigorous stirring. After 2h, the solvent is removed in vacuo, the residues treated with aqueouscitric acid (pH 3-4) and extracted with EtOAc (3×10 mL). The combinedorganic phases are dried over MgSO₄, concentrated to ˜5 mL and purifiedby flash chromatography on silica gel to afford the correspondinggabapentin acid adducts. Each adduct is divided into two equal portions,one of which is dissolved in methanol (5 mL) and stirred with excess ofa freshly prepared solution of diazomethane in diethyl ether. Afterstirring for 60 min, the solvent is removed in vacuo to afford themethyl ester analogs. These esters along with the remaining portions oftheir acid precursors are separately treated with 50% (v/v) TFA inCH₂Cl₂ for 30 min and the solvent removed in vacuo. The products areconverted to the corresponding sodium salts by dissolving each residuein 50% MeOH/H₂O (5 mL) and stirring with Na⁺ cation exchange resin(prepared from Dowex HCR-W2, ˜2 mmol) for 30 min. The resins are washedwith 50% MeOH/H₂O (3×5 mL) and the combined filtrates evaporated todryness to afford compounds (168)-(175).

Example 36

[0535] Synthesis of Compounds (196)-(211)

[0536] Compounds (96)-(99) (3 mmol each) are separately dissolved in dryacetonitrile (15 mL) together with DMAP (3 mmol). Solutions ofbromoacetic anhydride (3.5 mmol) in acetonitrile are added dropwise andthe reaction mixtures stirred for 4 h at room temperature. The solventis removed in vacuo, the residues redissolved in ethyl acetate andwashed thoroughly with a 0.2 M aqueous solution of KHSO₄. The organicphases are dried over MgSO₄ and evaporated to dryness to afford thecrude bromoacetates (176) and (177), and bromoacetamides (178) and(179), which are used as is in subsequent steps.

[0537] Solutions containing either 2 M ethylamine or benzylamine in dryDMSO (1 mL) are added separately to solutions of the bromoacetylcompounds (176)-(179) (2 mmol) in dry DMSO (4 mL). After stirring atroom temperature for 4 h, the solvent is removed in vacuo. The residuesare redissolved in ethyl acetate and washed with saturated NaHCO₃, waterand brine, then the organic layers evaporated to dryness. The resultingamine compounds (180)-(187) are used in the subsequent step withoutfurther purification.

[0538] Solutions containing O-trimethylsilyl-glycolic acid (1.1 mmol)and DIC (1.1 mmol) in DMF (1 mL) are separately added to solutions ofcompounds (180)-(187) (1 mmol each) in DMF (4 mL). After stirring for 2h at room temperature, the solutions are filtered and the solventremoved in vacuo. The residues are redissolved in ethyl acetate, washedthoroughly with 0.2 M aqueous KHSO₄, and the organic layers dried overMgSO₄ and evaporated to dryness. The resulting O-silyl-glycolamides areeach dissolved in CH₂Cl₂ containing pyridine-HF complex (1.5 mmol) andthe mixtures stirred for 2 h at room temperature. After removal of thesolvent in vacuo, the residues are purified by flash chromatography onsilica gel to afford glycolamides (188)-(195).

[0539] (188)-(195) (0.5 mmol each) are separately heated under refluxwith a toluene solution containing either acyl azide (39) or (43) (˜2.5mmol) for 14 h. After cooling to room temperature, the solvent isremoved in vacuo and the sixteen residues dissolved in EtOAc (20 mL),washed with water (2×10 mL) and dried over MgSO₄. The products arepurified by preparative TLC on silica gel plates. The eight cyanoethylester products are deprotected by treatment with 20% piperidine/CH₂Cl₂(2 mL) for 30 min and the solvent removed in vacuo. The sixteentert-butyl esters are treated with 50% (v/v) TFA in CH₂Cl₂ for 30 minand the solvent removed in vacuo. The acids are converted to thecorresponding sodium salts by dissolving each compound in 50% MeOH/H₂O(5 mL) and stirring with Na⁺ cation exchange resin (prepared from DowexHCR-W2, ˜2 mmol) for 30 min. The resins are washed with 50% MeOH/H₂O(3×5 mL) and the combined filtrates evaporated to dryness to affordcompounds (196)-(211).

Example 37

[0540] Synthesis of Compounds (221)-(228)

[0541] Solutions of compounds (96) and (97) (2 mmol each) in dry CH₂Cl₂(20 mL) and pyridine (2 mL) are cooled to 0° C. and separately treatedwith 4-nitrophenyl chloroformate (2 mmol) with stirring for 2 h. Thesolutions are washed with saturated NaHCO₃, water and brine and theorganic layers evaporated to dryness. The residues are purified by flashchromatography on silica gel to afford the intermediate 4-nitrophenylcarbonates. Each product is separately dissolved in dioxane (10 mL) anda solution of GABA (2 mmol) in aqueous phosphate buffer at pH ˜8.5 (2mL) added to each with vigorous stirring. After 2 h, the solvent isremoved in vacuo, the residues treated with aqueous citric acid (pH 3-4)and extracted with EtOAc (3×15 mL). The combined organic phases aredried over MgSO₄, concentrated to ˜5 L and purified by flashchromatography on silica gel to afford the corresponding acids (215) and(216).

[0542] A suspension of mercuric oxide (1 mmol) and each of (215) and(216) (2 mmol) in CH₂Cl₂ (15 mL) are separately stirred overnight atroom temperature. 2 mmol of either (56) or (57) is added to thesesuspensions and stirring continued for 24 h. The four solutions arewashed with saturated NaHCO₃, water and brine and the organic layersevaporated to dryness. The residues are purified by flash chromatographyon silica gel to afford carbonates (217)-(220).

[0543] (217)-(220) (1 mmol each) are dissolved in dioxane (10 mL) and asolution of gabapentin (2) (1 mmol) in aqueous phosphate buffer at pH˜8.5 (1 mL) added to each with vigorous stirring. After 2 h, the solventis removed in vacuo, the residues treated with aqueous citric acid (pH3-4) and extracted with EtOAc (3×10 mL). The combined organic phases aredried over MgSO₄, concentrated to ˜5 mL and purified by flashchromatography on silica gel to afford the corresponding gabapentin acidadducts. Each adduct is divided into two equal portions, one of which isdissolved in methanol (5 mL) and stirred with excess of a freshlyprepared solution of diazomethane in diethyl ether. After stirring for60 min, the solvent is removed in vacuo to afford the correspondingmethyl ester analogs. These esters along with the remaining portions oftheir acid precursors are separately treated with 50% (v/v) TFA inCH₂Cl₂ for 30 min and the solvent removed in vacuo. The products areconverted to the corresponding sodium salts by dissolving each residuein 50% MeOH/H₂O (5 mL) and stirring with Na⁺ cation exchange resin(prepared from Dowex HCR-W2, ˜2 mmol) for 30 min. The resins are washedwith 50% MeOH/H₂O (3×5 mL) and the combined filtrates evaporated todryness to afford compounds (221)-(228).

Example 38

[0544] Synthesis of Compound (230)

[0545] Cholic acid (6) (2 g, 4.9 mmol) was dissolved in anhydrousacetone (50 mL) and tert-butyl bromoacetate (0.87 mL, 5.9 mmol) andpowdered K₂CO₃ (1.4 g, 9.8 mmol) added. The solution was heated underreflux overnight and then cooled to room temperature. The mixture wasfiltered and the filtrate concentrated to a small volume. The protectedglycolate product (229) was isolated as a white solid after purificationby flash chromatography on silica gel, eluting with CH₂Cl₂/MeOH (95/5).Compound (229) (160 mg, 0.26 mmol) was dissolved in 60% (v/v) TFA/CH₂Cl₂and stirred for 2 h at room temperature. After removal of the solvent invacuo the residue was treated with water and extracted with ethylacetate. The organic layer was dried and concentrated in vacuo. Thisresidue was treated with 25% (v/v) piperidine/CH₂Cl₂ for 1 h to saponifyany trifluoroacetate ester formed during the TFA deprotection step.After removal of the piperidine/CH₂Cl₂ in vacuo, the product wasextracted with ethyl acetate, washed with aqueous citric acid solution,dried over MgSO₄ and concentrated in vacuo. This crude acid product wasdissolved in dry THF (10 mL), NEt₃ (47 μL, 0.34 mmol) added and thesolution cooled to −5° C. in an ice-salt bath. Ethyl chloroformate (19μL, 0.2 mmol) was added slowly, maintaining the temperature between −5to 0° C. After addition was completed, the cold mixture was stirred foran additional 30 minutes. A solution containing gabapentin (2) (57 mg,0.34 mmol) and NaHCO₃ (28 mg, 0.34 mmol) in water (1 mL) was added tothis mixture and stirred at for 30 minutes at 0° C. and then at roomtemperature for an additional 30 minutes. The pH of the solution wasadjusted to 3-4 by addition of citric acid and the mixture extractedwith ethyl acetate (2×20 mL). The organic layer was dried over MgSO₄ andconcentrated in vacuo. The product (230) (50 mg, 50% yield) was isolatedafter purification by flash chromatography on silica gel, eluting withEtOAc/MeOH (90/10).

[0546] MS (ESI): m/z=620.5 (M+H⁺).

[0547]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 4.55 (s,2H), 3.34 (s, 2H), 2.29 (s, 2H), 1.02 (d, 3H, J=6.4 Hz), 0.91 (s, 3H),0.71(s, 3H).

Example 39

[0548] Synthesis of Compound (232)

[0549] Cholic acid (6) (490 mg, 1.2 mmol) and NEt₃ (145 μL, 2 mmol) weredissolved in dry THF (20 mL) and trichlorobenzoyl chloride (292 mg, 1.2mmol) added. After stirring for 30 minutes tert-butyl (R)-lactate (150mg, 1 mmol) was added followed by catalytic DMAP (20 mg). The reactionmixture was stirred for 16 h at room temperature and the solvent removedin vacuo. The residue was treated with aqueous citric acid and extractedinto ethyl acetate. The organic phase was dried over MgSO₄ andconcentrated in vacuo. The protected lactate product (231) (450 mg, 84%yield) was purified by flash chromatography on silica gel, eluting withEtOAc/MeOH (97/3). Compound (231) was dissolved in 40% (v/v) TFA/CH₂Cl₂and stirred for 2 h at room temperature. After removal of the solvent invacuo the residue was treated with water and extracted with ethylacetate. The organic layer was dried and concentrated in vacuo. Thisresidue was treated for 1 h with 25% (v/v) piperidine/CH₂Cl₂ to saponifyany trifluoroacetate ester formed during the TFA deprotection step.After removal of the piperidine/CH₂Cl₂ in vacuo, the lactic acidconjugate was extracted with ethyl acetate, washed with aqueous citricacid solution, dried over MgSO₄ and concentrated in vacuo. To 590 mg ofthis product (1.2 mmol) was added dry THF (20 mL), NEt₃ (335 μL, 2.4mmol) and the solution cooled to −5° C. in an ice-salt bath. Ethylchloroformate (140 μL, 1.5 mmol) was added slowly, maintaining thetemperature between −5 to 0° C. After addition was completed, the coldmixture was stirred for an additional 30 minutes. A solution containinggabapentin (2) (412 mg, 2.4 mmol) and NaHCO₃ (336 mg, 4 mmol) in water(5 mL) was added to this mixture and stirred at for 30 minutes at 0° C.and then at room temperature for an additional 30 minutes. The pH of thesolution was adjusted to 3-4 by addition of citric acid and the mixtureextracted with ethyl acetate (3×30 mL). The organic layer was dried overMgSO₄ and concentrated in vacuo. The product (232) (250 mg, 32% yield)was isolated after purification by flash chromatography on silica gel,eluting with EtOAc/MeOH (97/3).

[0550] MS (ESI): m/z=634.5 (M+H⁺).

[0551]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 5.03 (q,1H, J=6.8 Hz), 3.34 (s, 2H), 2.29 (s, 2H), 1.42 (d, 3H, 3=6.8 Hz), 101(d, 3H, J=6.4 Hz), 0.91 (s, 3H), 0.71(s, 3H).

Example 40

[0552] Synthesis of Compound (234)

[0553] Cholic acid (6) (490 mg, 1.2 mmol) and NEt₃ (145 μL, 2 mmol) weredissolved in dry THF (20 mL) and trichlorobenzoyl chloride (292 mg, 1.2mmol) added. After stirring for 30 minutes benzyl (S)-lactate (180 mg, 1mmol) was added followed by catalytic DMAP (20 mg). The reaction mixturewas stirred for 16 h at room temperature and the solvent removed invacuo. The residue was treated with aqueous citric acid and extractedinto ethyl acetate. The organic phase was dried over MgSO₄ andconcentrated in vacuo. The protected lactate product (233) was purifiedby flash chromatography on silica gel, eluting with EtOAc/MeOH (97/3).Compound (233) (480 mg, 1 mmol) was dissolved in EtOAc (30 mL) andstirred with 5% Pd/C (50 mg) under 1 atm hydrogen gas for 6 h to removethe benzyl protecting group. After removal of the solvent in vacuo theresidue was dissolved in dry THF (20 mL), NEt₃ (335 μL, 2.4 mmol) wasadded and the solution cooled to −5° C. in an ice-salt bath. Ethylchloroformate (140 μL, 1.5 mmol) was added slowly, maintaining thetemperature between −5 to 0° C. After addition was completed, the coldmixture was stirred for an additional 30 minutes. A solution containinggabapentin (2) (412 mg, 2.4 mmol) and NaHCO₃ (336 mg, 4 mmol) in water(5 mL) was added to this mixture and stirred at for 30 minutes at 0° C.and then at room temperature for an additional 30 minutes. The pH of thesolution was adjusted to 3-4 by addition of citric acid and the mixtureextracted with ethyl acetate (3×30 mL). The organic layer was dried overMgSO₄ and concentrated in vacuo. The product (234) was isolated afterpurification by flash chromatography on silica gel, eluting withEtOAc/MeOH (97/3).

[0554] MS (ESI): m/z=634.5 (M+H⁺).

[0555]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 5.03 (q,1H, J=6.8 Hz), 3.34 (s, 2H), 2.29 (s, 2H), 1.43 (d, 3H, J=6.8 Hz), 1.01(d, 3H, J=6.4 Hz), 0.91(s, 3H), 0.71 (s, 3H).

Example 41

[0556] Synthesis of Compound (237)

[0557] Ursodeoxycholic acid (235) (825 mg, 2.1 mmol) and NEt₃ (1.1 mL, 8mmol) were dissolved in dry THF (35 mL) and the solution cooled to −5°C. in an ice-salt bath. Ethyl chloroformate (242 μL, 2.5 mmol) was addedslowly, maintaining the temperature between −5 to 0° C. After additionwas completed, the cold mixture was stirred for an additional 30minutes. A solution of HOBt (378 mg, 2.8 mmol) in dry THF (5 mL) wasadded and the solution stirred for 30 minutes at 0° C. A solution ofgabapentin (2) (684 mg, 4 mmol) in 2N NaOH (5 mL) was added to thismixture and stirred at for 30 minutes at 0° C. and then at roomtemperature for an additional 30 minutes. The pH of the solution wasadjusted to 3-4 by addition of citric acid and the mixture extractedwith ethyl acetate (3×50 mL). The organic layer was dried over MgSO₄ andconcentrated in vacuo. The product (236) (280 mg, 25% yield) wasisolated after purification by preparative HPLC, using a Waters Nova-PakC-18 column (19×300 mm) and eluting with a water/acetonitrile/0.05%formic acid gradient at 25 mL/min (30% MeCN ramping to 43% in 3 min,then to 53% MeCN by 22 min). Electrospray mass spectrometry showed theexpected molecular ion at m/z=???(M+H⁺). The corresponding sodium salt(237) was prepared in quantitative yield by stirring (236) with 1equivalent aqueous NaHCO₃ and lyophilization to dryness.

[0558] MS (ESI): m/z=546.49 (M+H⁺) and 544.54 (M−H⁻).

[0559]¹H NMR (CD₃OD, 400 MHz, characteristic resonances only): 3.30 (s,2H), 2.29 (s, 2H), 0.98 (d, 3H, J=6.4 Hz), 0.96 (s, 3H), 0.70 (s, 3H).

Example 42

[0560] In Vitro Compound Transport Assays with IBAT and LBAT-ExpressingCell Lines

[0561] (a) Inhibition of Radiolabeled Taurocholate Uptake

[0562] CHO cells transfected with either the IBAT or LBAT transporterwere seeded into 96-well microtiter plates at 100,000 cells/well in 100μL DMEM containing 10% serum, glutamine and Penstrep. After overnightincubation the media was removed and test compound (25 μL) added at 2×the final desired concentration. Tritiated taurocholate (50,000CPM/well) was diluted with cold substrate to a final concentration of 5μM and 25 μL/well of this mixture was added to the plate. Afterincubating for 1 h at room temperature the solution was removed and theplate washed 4× with PBS at 4° C. 200 μL/well of scintillant is addedand the plate then read in a Wallac microbeta counter. The inhibitiondata is processed by standard methods to calculate an inhibitionconstant K_(i) for the test compound.

[0563] (b) Analysis of Electrogenic Transport in Xenopus Oocytes RNAPreparation:

[0564] Human IBAT and LBAT Transporter cDNAs were subcloned into amodified pGEM plasmid that contains 5′ and 3′ untranslated sequencesfrom the Xenopus β-actin gene. These sequences increase RNA stabilityand protein expression. Plasmid cDNA was linearized and used as templatefor in vitro transcription (Epicentre Technologies transcription kit,4:1 methylated:non-methylated GTP).

[0565] Xenopus oocyte isolation. Xenopus laevis frogs were anesthetizedby immersion in Tricaine (1.5 g/mL in deionized water) for 15 min.Oocytes were removed and digested in frog ringer solution (90 mM NaCl, 2mM KCl, 1 mM MgCl₂, 10 mM NaHEPES, pH 7.45, no CaCl₂) with 1 mg/mLcollagenase (Worthington Type 3) for 80-100 min with shaking. Theoocytes were washed 6 times, and the buffer changed to frog ringersolution containing CaCl₂ (1.8 mM). Remaining follicle cells wereremoved if necessary. Cells were incubated at 16° C., and each oocyteinjected with 10-20 μg RNA in 45 μL solution.

[0566] Electrophysiology measurements. Transport currents were measured2-14 days after injection, using a standard two-electrodeelectrophysiology set-up (Geneclamp 500 amplifier, Digidata 1320/PCLAMPsoftware and ADInstruments hardware and software were used for signalacquisition). Electrodes (2-4 mΩ) were microfabricated using a SutterInstrument puller and filled with 3M KCl. The bath was directly grounded(transporter currents were less than 0.3 μA). Bath flow was controlledby an automated perfusion system (ALA Scientific Instruments, solenoidvalves).

[0567] For transporter pharmacology, oocytes were clamped at −60 to −90mV, and continuous current measurements acquired using PowerLab Softwareand an ADInstruments digitizer. Current signals were lowpass filtered at20 Hz and acquired at 4-8 Hz. All bath and drug-containing solutionswere frog ringers solution containing CaCl₂. Drugs were applied for10-30 seconds until the induced current reached a new steady-statelevel, followed by a control solution until baseline currents returnedto levels that preceded drug application. The difference current(baseline subtracted from peak current during drug application)reflected the net movement of charge resulting from electrogenictransport and was directly proportional to tranport rate. Recordingswere made from a single oocyte for up to 60 min, enabling 30-40 separatecompounds to be tested per oocyte. Compound-induced currents weresaturable and gave half-maximal values at substrate concentrationscomparable to radiolabel competition experiments. To compare resultsbetween oocytes expressing different levels of transport activity, asaturating concentration of glycodeoxycholate (100 μM) was used as acommon reference to normalize results from test compounds. Using thisnormalization procedure V^(max) (i.e. maximal induced current) fordifferent compounds at 100 μM tested on different oocytes could becompared. TABLE 1 In vitro transport data for selected compounds onIBAT-expressing cells % Max. COMPOUND IC₅₀ (M) EC₅₀ (M) (GDC)  (8) 36 7067  (13) 66 22 67 (124) 7 58 28 (125) >100 >100 0 (230) 4 30 83 (232) 1225 70 (234) 5.6 16 76 (237) ND 67 60

[0568] TABLE 2 In vitro transport data for selected compounds onLBAT-expressing cells % Max. COMPOUND IC₅₀ (M) EC₅₀ (M) (GDC)  (8) 8 1938  (13) 64 ND 38 (124) 1.7 ND ND (125) 0.7 31 140  (230) 2.3 ND ND(232) 4.1 ND ND (234) 1.6 ND ND

Example 43

[0569] In Vitro Uptake of (8) by CHO Cells Transfected with IBAT or LBATEvaluated by LC—MS/MS

[0570] Active transport of (8) by the bile acid transport system wasevaluated in vitro by incubation of (8) or glycocholate (controlsubstrate) with untransfected CHO K1 cells or CHO cells transfected witheither IBAT or LBAT. Cells (10⁵ cells/mL) were incubated in 96 wellplates with varying concentrations (0.06 to 1000 μM) of (8) orglycocholate for 10 min. Cells were then washed with Hank's BalancedSalt Solution (HBSS) and lysed and extracted by addition of 100 μL ofwater followed by sonication. Concentrations of (8) or glycocholate incell extracts were determined by direct injection onto an API 2000LC/MS/MS equipped with an Agilent 1100 binary pump and autosampler.Separation was achieved using a Keystone BDS Hypersil 2×50 mm columnheated to 45° C. during the analysis. The mobile phases were: 0.1%formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Thegradient condition was: 5% B for 1 min, increasing to 90% B in 0.2 min,maintained for 2.8 min and returning to 5% B for 2 min. A TurbolonSpraysource was used on the API 2000. The analysis was performed in thepositive ion mode and MRM transitions of 466/412 and 562/154 were usedin the analysis of glycocholate and (8), respectively. Ten microlitersof the cell extracts were injected. Peaks were integrated using Analystquantitation software. The method was linear for (8) or glycocholateover the concentration range 0.039 to 10 μM. FIG. 9 shows therelationship between the substrate concentration and the rate of uptakeof (8) or glycocholate into IBAT transfected cells (the backgroundnon-specific uptake of these compounds into untransfected CHO K1 cellswas subtracted to provide specific active uptake). Similarly, FIG. 10shows the relationship between the substrate concentration and the rateof uptake of (8) or glycocholate into LBAT transfected cells (thebackground non-specific uptake of these compounds into untransfected CHOK1 cells was subtracted to provide specific active uptake). Activeuptake of (8) was observed for both bile acid transport systemsindicating the potential for enterohepatic recirculation of the prodrug.

Example 44

[0571] In Vitro Enzymatic Release of Gabapentin (2) from (8)

[0572] Sustained oral delivery of a drug molecule by attachment througha cleavable linker arm to an actively transported promoiety requiresthat the drug eventually be released from the drug/cleavablelinker/transporter compound (prodrug) by enzymatic cleavage in one ormore tissues of the enterohepatic circulation. The release of gabapentinfrom the prodrug (8) was evaluated in vitro using tissues representativeof those involved in the enterohepatic circulation. Tissues wereobtained from commercial sources (e.g., Pel-Freez Biologicals, Rogers, AR, or GenTest Corporation, Woburn, Mass.). Stability of (8) towardsspecific enzymes (e.g., carboxypeptidase A, cholylglycine hydrolase) wasalso evaluated by incubation with the purified enzyme. Experimentalconditions used for the in vitro studies are described in Table 3 below.Each preparation was incubated with (8) at 37° C. for one hour. Aliquots(50 μL) were removed at 0, 30, and 60 min and quenched with 0.1%trifluoroacetic acid in acetonitrile. Samples were then centrifuged andanalyzed by LC/MS/MS as described in Example 43. Gabapentin wasquantified using MRM transition of 172.0/137.2. The data indicate a slowrate of hydrolysis of (8) in plasma, liver, or intestine resulting information of gabapentin. Substantially faster release of gabapentin wascatalyzed by cholylglycine hydrolase (the naturally occurring bacterialenzyme responsible for hydrolysis of glycocholate in vivo). TABLE 3 InVitro Enzymatic Release of Gabapentin from (8) Percent of GabapentinSubstrate Released in 60 Preparation Concentration Cofactors min RatPlasma 2.0 μM None 0.55 Human Plasma 2.0 μM None 0.31 Rat Liver S9 2.0μM NADPH 1.67 (0.5 mg/mL) Human Liver S9 2.0 μM NADPH 4.89 (0.5 mg/mL)Human Intestine S9 2.0 μM NADPH 1.31 (0.5 mg/mL) Cholylglycine 0.8 μMNone 35.31 Hydrolase (87 units/mL) Carboxypeptidase A 2.0 μM None Stable(10 units/mL)

Example 45

[0573] Sustained Release of Gabapentin from (8) Following OralAdministration to Rats

[0574] The pharmacokinetics of the prodrug (8) were examined in rats.Three groups of four male Sprague-Dawley rats (approx 200 g) withjugular cannulae each received one of the following treatments: A) asingle bolus intravenous injection of gabapentin (25 mg/kg, as asolution in water); B) a single oral dose of gabapentin (25 mg/kg, as asolution in water) administered by oral gavage; C) a single oral dose of(8) (85.25 mg/kg, as a solution in water) administered by oral gavage.Animals were fasted overnight prior to dosing and until 4 hourspost-dosing. Serial blood samples were obtained over 24 hours followingdosing and blood was processed for plasma by centrifugation. Plasmasamples were stored at −80° C. until analyzed. Concentrations of (8) orgabapentin in plasma samples were determined by LC/MS/MS as described inExample 44. Plasma (50 μL) was precipitated by addition of 100 mL ofmethanol and supernatent was injected directly onto the LC/MS/MS system.The method was linear for gabapentin over the concentration range 0.001to 20 ng/mL and for (8) over the concentration range 0.01 to 10 ng/mL.Following oral administration of gabapentin, concentrations ofgabapentin in plasma reached a maximum at 2.8±2.5 hours (T_(max)) anddeclined thereafter with a terminal half-life of 2.4±0.5 hours. The oralbioavailability of gabapentin was 87±18%. Following oral administrationof (8), concentrations of intact (8) in plasma reached a maximum at ˜8hours post-dosing and were sustained out to 24 hours (terminalhalf-life>12 hours). Concentrations of released gabapentin in plasmawere similarly sustained out to 24 hours (half-life>12 hours). Thesedata indicate that prodrug (8) is metabolized to gabapentin in vivo, andthat substantially sustained release of gabapentin was achievedfollowing oral administration of (8) compared to the relatively rapidclearance observed for oral gabapentin.

Example 46

[0575] Secretion of (8) in Bile Following Oral Administration to Rats

[0576] Sustained release of gabapentin from a prodrug that is subject toenterohepatic recirculation requires that a proportion of the intactprodrug be absorbed after oral administration and subsequently secretedinto the bile intact. The potential for enterohepatic recirculation ofintact (8) was examined in rats with indwelling bile duct fistulae. Agroup of four male Sprague-Dawley rats (approx. 200 g) cannulated inboth the jugular vein and the common bile duct each received a singleoral dose of (8) (85.25 mg/kg, as a solution in water) by oral gavage.Serial blood samples were obtained over 24 hours following dosing andblood was processed for plasma by centrifugation. Bile was collectedcontinuously in aliquots over 24 hours. Plasma and bile samples werefrozen at −80° C. until analyzed. Concentrations of (8) or gabapentin inplasma samples were deermined by LC/MS/MS as described in Example 45.Concentrations of intact (8) in bile were similarly determined byLC/MS/MS. Bile (20 μL) was diluted 1:1000 with methanol and injecteddirectly onto the HPLC system. Concentrations of (8) in bile reached amaximum at ˜6 hours post-dosing and were sustained up to 24 hours. Thesedata indicate that (8) was successfully transported across the intestineby the ileal bile acid transport system (IBAT) and further secreted intothe bile by the liver bile acid transporter (LBAT). However, nogabapentin was detected in plasma of bile duct-cannulated rats,indicating that cleavage of the prodrug was dependent on enterohepaticrecirculation.

[0577] In view of the above disclosure, it is understood, of course,that combinations of substituents within the compounds of the presentinvention do not include any combination that is chemically impossibleor non-feasible as would be appreciated by one skilled in the art.

What is claimed is:
 1. A method for achieving sustained therapeutic orprophylactic blood concentrations of a GABA analog or an activemetabolite thereof in the systemic circulation of an animal which methodcomprises orally administering to said animal a compound of formula (I):

Wherein: R¹ and R²are independently hydrogen or hydroxy; X is selectedfrom the group consisting of hydroxy and D—Q^(a)—(T)— Wherein: T is —O—or —NH—; Q^(a) is a covalent bond or a linking group that may cleaveunder physiological conditions to release a GABA analog or activemetabolite thereof into the systemic blood circulation of said animal,wherein said linking group is not a linear oliogopeptide comprising 1, 2or 3 α-amino acids and/or β-amino acids; and D is a GABA analog moiety Zis selected from the group consisting of (a) a substituted alkyl groupcontaining a moiety which is negatively charged at physiological pHwhich moiety is selected from the group consisting of —COOH, —SO₃H,—SO₂H, —P(O)(OR¹⁹)(OH), —OP(O)(OR¹⁹)(OH), —OSO₃H, wherein R¹⁹ isselected from the group consisting of alkyl, substituted alkyl, aryl andsubstituted aryl; and (b) a group of the formula: —M—Q^(b)—D′ Wherein: Mis selected from the group consisting of —CH₂OC(O)— and —CH₂CH₂C(O)—;Q^(b) is a covalent bond or a linking group which may cleave underphysiological conditions to release a GABA analog or active metabolitethereof into the systemic blood circulation of said animal, wherein saidlinking group is not a linear oligopeptide consisting of 1, 2 or 3α-amino acids and/or β-amino acids; and D′ is a GABA analog moietyprovided that when X is hydroxy, then Z is a group of the formula—M—Q^(b)—D′.
 2. The method of claim 1 wherein D is a GABA analog moietypreferably of the formula:

And D′ is a GABA analog moiety preferably of the formula:

Wherein: R³ is selected from the group consisting of hydrogen, anamino-protecting group, or a covalent bond linking the GABA analogmoiety to Q^(a); R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms towhich they are attached form a heterocyclic ring; R⁵ and R⁶ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl; R⁷ and R⁸ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl, or R⁷ and R⁸ together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclic or substituted heterocyclic ring; R⁹ is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl; R¹¹ is selected from the group consisting ofcarboxylic acid, carboxylic amide, carboxylic ester, sulfonamide,phosphonic acid, acidic heterocycle, sulfonic acid, hydroxamic acid andC(O)R¹²; R¹² is a covalent bond linking the GABA analog moiety to Q^(a),provided only one of R³ and R¹² links D to Q^(a); R^(3′) is selectedfrom the group consisting of hydrogen, an amino-protecting group, or acovalent bond linking the moiety to Q^(b); R^(4′) is hydrogen, or R^(4′)and R^(9′) together with the atoms to which they are attached form aheterocyclic ring; R^(5′) and R^(6′) are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; R^(7′) and R^(8′) are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, alkynyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl, or R^(7′) and R^(8′) together with the atoms to which theyare attached form a cycloalkyl, substituted cycloalkyl, heterocyclic orsubstituted heterocyclic ring; R^(9′) is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl; R^(10′)is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; R^(11′) is selected from the group consisting ofcarboxylic acid, carboxylic amide, carboxylic ester, sulfonamide,phosphonic acid, acidic heterocycle, sulfonic acid, hydroxamic acid andC(O)R¹²; R^(12′) is a covalent bond linking the GABA analog moiety toQ^(b), provided only one of R^(3′) and R^(12′) links D′ to Q^(b); or apharmaceutically acceptable salt thereof.
 3. The method according toclaim 1 wherein R¹ and R² are both α-OH; or R¹ is β-OH and R² ishydrogen; or R¹ is α-OH and R² is hydrogen; or R¹ is hydrogen and R² isα-OH; or R¹ is β-OH and R² is α-OH; or R¹ and R² are both hydrogen. 4.The method according to claim 2 wherein D—Q^(a)—(T)— and/or —M—Q^(b)—D′are selected to cleave under physiological conditions at a rate toprovide a therapeutic and/or prophylactic blood concentration of theGABA analog or active metabolite thereof in the animal for a period ofat least about 10% longer than when the GABA analog is orally deliveredby itself at an equivalent dose.
 5. A compound of formula (I):

Wherein: R¹ and R² are independently hydrogen or hydroxy; X is selectedfrom the group consisting of hydroxy and D—Q^(a)—(T)— Wherein: T is —Oor —NH—; Q^(a) is a covalent bond or a linking group; and D is a GABAanalog moiety preferably of the formula:

Where: R³ is selected from the group consisting of hydrogen, anamino-protecting group, or a covalent bond linking the GABA analogmoiety to Q^(a); R⁴ is hydrogen, or R⁴ and R⁹ together with the atoms towhich they are attached form a heterocyclic ring; R⁵ and R⁶ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl; R⁷ and R⁸ areindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl, or R⁷ and R⁸ together with the atoms towhich they are attached form a cycloalkyl, substituted cycloalkyl,heterocyclic or substituted heterocyclic ring; R⁹ is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;R¹⁰ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl; R¹¹ is selected from the group consisting ofcarboxylic acid, carboxylic amide, carboxylic ester, sulfonamide,phosphonic acid, acidic heterocycle, sulfonic acid, hydroxamic acid andC(O)R¹²; R¹² is a covalent bond linking the GABA analog moiety to Q^(a),provided only one of R³ and R¹² links D to Q^(a); Z is selected from thegroup consisting of (a) a substituted alkyl group containing a moietywhich is negatively charged at physiological pH which moiety is selectedfrom the group consisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR¹⁹)(OH),—OP(O)(OR¹⁹)(OH), —OSO₃H, wherein R¹⁹ is selected from the groupconsisting of alkyl, substituted alkyl, aryl and substituted aryl; and(b) a group of the formula: —M—Q^(b)—D′ Wherein: M is selected from thegroup consisting of —CH₂OC(O)— and —CH₂CH₂C(O)—; Q^(b) is a covalentbond or a linking group which may cleave under physiological conditionsto release a GABA analog or active metabolite thereof into the systemicblood circulation of said animal; and D′ is a GABA analog moietypreferably of the formula:

Wherein: R^(3′) is selected from the group consisting of hydrogen, anamino-protecting group, or a covalent bond linking the GABA analogmoiety to Q^(b); R^(4′) is hydrogen or R^(4′) and R^(9′) together withthe atoms to which they are attached form a heterocyclic ring; R^(5′)and R^(6′) are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;R^(7′) and R^(8′)are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substitutedaryl, heteroaryl and substituted heteroaryl, or R^(7′) and R^(8′)together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclic or substituted heterocyclic ring;R^(9′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, heteroaryland substituted heteroaryl; R^(10′) is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl; R^(11′)is selected from the group consisting of carboxylic acid, carboxylicamide, carboxylic ester, sulfonamide, phosphonic acid, acidicheterocycle, sulfonic acid, hydroxamic acid and C(O)R¹²; R^(12′) is acovalent bond linking the GABA analog moiety to Q^(b), provided only oneof R^(3′) and R^(12′) links D to Q^(b); or a pharmaceutically acceptablesalt thereof; provided that when X is hydroxy, then Z is a group of theformula —M—Q^(b)—D′; and further provided that when X is hydroxy, M is—CH₂CH₂C(O)—, Q^(b) is a covalent bond and R^(11′) is carboxylic acid,then at least one of R^(5′), R^(6′), R^(7′), R^(8′), R^(9′) and R^(10′)is other than hydrogen; and yet further provided that neither Q^(a) norQ^(b) is a linear oligopeptide comprised exclusively of 1, 2 or 3α-amino acids and/or β-amino acids.
 6. A compound of formula (II):

Wherein: R¹ and R² are both α-OH; R¹ is β-OH and R² is hydrogen; R¹ isα-OH and R² is hydrogen; Rl is hydrogen and R² is α-OH; R¹ is β-OH andR² is α-OH; or R¹ and R² are both hydrogen; A is —O— or —CH₂—; D″ is aGABA analog moiety selected from the group consisting of:

Where R^(3′) is hydrogen or a covalent bond linking D″ to Q^(b); R^(11′)is carboxyl acid or C(O)R^(12′), wherein R^(12′) is a covalent bondlining D″ to Q^(b); and Q^(b) is a covalent bond or a linker which maycleave under physiological conditions to release a GABA analog or anactive metabolite thereof thereby providing a therapeutic orprophylactic systemic blood concentration of said GABA analog or anactive metabolite thereof in said animal, wherein said linker is not alinear oligopeptide consisting of 1, 2 or 3 α-amino acids and/or β-aminoacids; or a pharmaceutically acceptable salt thereof.
 7. The compoundaccording to claim 6, wherein Q^(b) is a linker.
 8. The compoundaccording to claim 7, wherein Q^(b) is a group of formula:—[E—(F*)_(n)—G]_(m)— Wherein: m is an integer of from 1 to 4; n is 0 or1; E is —NH— or —O—; F* is selected from a group consisting of alkylene,substituted alkylene, alkenylene, substituted alkenylene, alkynylene,substituted alkynylene, cycloalkylene, substituted cycloalkylene,cycloalkenylene, substituted cycloalkenylene, arylene, substitutedarylene, heteroarylene, substituted heteroarylene, heterocyclene andsubstituted heterocyclene; and G is —OC(O)—, —C(O)— or —NH—.
 9. Thecompound according to claim 8, wherein F* is selected from a groupconsisting of alkylene, alkynylene and alkylene substituted with a groupselected from the group consisting of —COOH, —SO₃H, —SO₂H,—P(O)(OR¹⁹)(OH), —OP(O)(OR¹⁹)(OH), —OSO₃H, wherein R¹⁹ is selected fromthe group consisting of alkyl, substituted alkyl, aryl and substitutedaryl; and where one, two or three methylene groups are optionallyreplaced by a carboxy (—C(O)O—) group.
 10. The compound according toclaim 7 wherein Q^(b) is a cleavable linker selected from the groupconsisting of structures of formulae (vi) to (x):

Wherein: V and V* are independently NR²⁰, O, S or CR²¹R²²; U is NR²⁰, O,S; R²⁵ is R²¹ or (CR²¹R²²)_(i)Z; Z is selected from the group consistingof —CO₂H, —SO₃H, —OSO₃H, —SO₂H, —P(O)(OR¹⁹)(OH), —OP(O)(OR¹⁹)(OH); s is0 or 1; r is 0, 1 or 2; k is 0, 1, 2, 3 or 4; each q is 1, 2, 3 or 4; lis 0 or 1; R¹⁹ is selected from the group consisting of alkyl,substituted alkyl, substituted aryl and substituted aryl; R²⁰, R²¹ andR²² are independently hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl or R²¹ and R²²together with the atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, heterocyclyl or substituted heterocyclyl ring,or, when R²⁰ and R²² are present and are on adjacent atoms, thentogether with the atoms to which they are attached form a heterocyclylor substituted heterocyclyl ring; R²³ and R²⁴ are independentlyhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R²³ and R²⁴ together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; provided thatwhen Q^(b) is of formula (vii), V and V* are NR²⁰, s is 1, k is 0 or 1,each q is either 1 or 2, and r is 0, 1 or 2 then R²⁵ is Z.
 11. Acompound of formula (IIIa):

Wherein: R¹ and R² are both α-OH; R¹ is β-OH and R² is hydrogen; R¹ isα-OH and R² is hydrogen; R¹ is hydrogen and R² is α-OH; R¹ is β-OH andR² is α-OH; or R¹ and R² are both hydrogen; T is —O— or —NH—and iseither α- or β-; D is a GABA analog moiety selected from the groupconsisting of:

Where R³is hydrogen or a covalent bond linking D to Q′; R¹¹ is carboxylor C(O)R¹², wherein R¹² is a covalent bond linking D to Q′, providedthat only one of R³ and R¹² is a covalent bond linkidng D to Q′;and Q′is a covalent bond or a linker which may cleave under physiologicalconditions to release a GABA analog or an active metabolite thereofthereby providing a therapeutic or prophylactic systemic bloodconcentration of said GABA analog or an active metabolite thereof insaid animal, wherein said linking group is not a linear oligopeptideconsisting of 1, 2 or 3 α-amino acids and/or β-amino acids; R¹³ is asubstituted alkyl group containing a moiety which is negatively chargedat physiological pH which moiety is selected from a group consisting of—COOH, —SO₃H, —SO₂H, —P(O)(OR¹⁹)(OH), —OP(O)(OR¹⁹)(OH), —OSO₃H, whereinR¹⁹ is selected from the group consisting of alkyl, substituted alkyl,aryl and substituted aryl; or a pharmaceutically acceptable saltthereof.
 12. The compound according to claim 11, wherein R¹³ is—CH₂CH₂CO₂H, —CH₂CH₂C(O)NHCH₂COOH, —CH₂CH₂C(O)NH—(CH₂)₂SO₃H,—CH₂CH₂CO₂Na, —CH₂CH₂C(O)NHCH₂COONa or —CH₂CH₂C(O)NH(CH₂)₂SO₃Na.
 13. Thecompound according to claim 11, wherein Q′ is a group of formula:—E′—(F′)_(n1)—G′— Where: n1 is 0 or 1; G′ is —C(O)—, alkylene, —O—C(O)—,—NRC(O)—, where R is hydrogen, alkyl or substituted alkyl; F′ isselected from a group consisting of a covalent bond, alkylene,substituted alkylene, alkenylene, substituted alkenylene, alkynylene,substituted alkynylene, cycloalkylene, substituted cycloalkylene,cycloalkenylene, substituted cycloalkenylene, arylene, substitutedarylene, heteroarylene, substituted heteroarylene, heterocyclene andsubstituted heterocyclene; and E′ is a covalent bond, —C(O)O— or —C(O)—.14. The compound according to claim 11, wherein Q′ is a cleavable linkerselected from the group consisting of —C(O)— and the structures offormulae (i) through (v) as shown below;

Wherein: V is selected from the group consisting of NR²⁰, O, S andCR²¹R²²; each s is independently 0 or 1; r is 0, 1, 2, 3 or 4; each q is1, 2, 3, 4, 5 or 6; each R²⁰ is independently hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl; each R²¹ and R²² is independently hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substitutedheterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroarylor R²¹ and R²² together with the atoms to which they are attached form acycloalkyl, substituted cycloalkyl, heterocyclyl or substitutedheterocyclyl ring, or, when R²⁰ and R²² are present and are on adjacentatoms, then together with the atoms to which they are attached form aheterocyclyl or substituted heterocyclyl ring; each R²³ and R²⁴ areindependently hydrogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl or R²³ and R²⁴ together withthe atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring; provided thatwhen Q′ is of formulae (i) or (ii), then when each V is NR²⁰ and each qis 1 or 2 then r is not 1, 2 or
 3. 15. A compound of formula (IIIb):

Wherein: R¹ and R² are both α-OH; R¹ is β-OH and R² is hydrogen; R¹ isα-OH and R² is hydrogen; R¹ is hydrogen and R² is α-OH; R¹ is β-OH andR² is α-OH; or R¹ and R² are both hydrogen; T is —O— or —NH—and iseither alpha or beta; D is a GABA analog moiety selected from the groupconsisting of:

Where R³ is hydrogen or a covalent bond linking D to Q″; R¹¹ is carboxylor C(O)R¹², wherein R¹² is a covalent bond linking D to Q″, providedthat only one of R³ and R¹² is a covalent bond linking D to Q″; R¹⁵ ishydrogen or an amino protecting group which is hydrolysable in vivo; andQ″ is a covalent bond or a linker which may cleave under physiologicalconditions to release a GABA analog or an active metabolite thereofthereby providing a therapeutic or prophylactic systemic bloodconcentration of said GABA analog or an active metabolite thereof insaid animal, wherein said linker is not a linear oligopeptide consistingof 1, 2 or 3 α-amino acids and/or β-amino acids; R¹⁴ is carboxyl oralkylamido substituted with a substituent selected from the groupconsisting of —COOH, —SO₃H, —SO₂H, —P(O)(OR¹⁹)(OH), —OP(O)(OR¹⁹)(OH),—OSO₃H, wherein R¹⁹ is selected from the group consisting of alkyl,substituted alkyl, aryl and substituted aryl; or a pharmaceuticallyacceptable salt thereof.
 16. A compound according to claim 15, whereinR¹⁴ is —CO₂H, —C(O)NHCH₂CO₂H, —C(O)NH(CH₂)₂SO₃H, —C(O)ONa,—C(O)NHCH₂CO₂Na or —C(O)NH(CH₂)₂SO₃Na.
 17. The compound according toclaim 16, wherein R¹⁵ is hydrogen, —C(O)—O—R¹⁶, wherein R¹⁶ is selectedfrom the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic and —C(O)(CR²¹R²²)NHR²⁰ where: R²⁰ isindependently hydrogen, alkyl, substituted alkyl alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl; R²¹ and R²² is independentlyhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl or R²¹ and R²² together with theatoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, heterocyclyl or substituted heterocyclyl ring, or, when R²⁰and R²² are present and are on adjacent atoms, then together with theatoms to which they are attached form a heterocyclyl or substitutedheterocyclyl ring.
 18. A compound selected from the group consisting of:

where R¹ and R² are independently hydrogen or hydroxy; orpharmaceutically acceptable salts thereof.
 19. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound according to any of claims 1, 5, 6, 11, 15, or
 18. 20. A methodfor treating a disease condition in a mammal, wherein said diseasecondition is selected from epilepsy, faintness attacks, hypokinesia,cranial disorders, neurodegenerative disorders, depression, anxiety,panic, pain, neuropathic pain, neuropathological disorders,gastrointestinal damage, inflammation and irritable bowel disease, whichmethod comprises administering to said mammal a pharmaceuticalcomposition according to claim 19.